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Conserved domains on  [gi|294979209|ref|NP_001171100|]
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growth factor receptor-bound protein 10 isoform 2 [Mus musculus]

Protein Classification

SHC-transforming protein; GRB/APBB1IP family PH domain-containing protein( domain architecture ID 13006570)

SHC-transforming protein is a signaling adapter containing two distinct phosphotyrosine-recognition modules, a C-terminal Src homology 2 (SH2) domain and an N-terminal phosphotyrosine-binding (PTB) domain, that may function in coupling activated growth factor receptors to signaling pathways| GRB/APBB1IP family PH (pleckstrin homology) domain-containing protein similar to PH region of Homo sapiens amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP) and growth factor receptor-bound protein 10 (GRB10)

Graphical summary

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List of domain hits

Name Accession Description Interval E-value
SH2_Grb10 cd10415
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) ...
434-541 1.66e-70

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb10 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


:

Pssm-ID: 198278  Cd Length: 108  Bit Score: 221.05  E-value: 1.66e-70
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd10415    1 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFSLDDGNTKFSD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd10415   81 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 108
PH_APBB1IP cd01259
Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin ...
234-356 1.49e-62

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.


:

Pssm-ID: 269961  Cd Length: 124  Bit Score: 200.93  E-value: 1.49e-62
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 234 NTSSCPEIQGFLQVKEVGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIFYLIAGKKQYNAPNEHGMCIK 313
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80
                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 294979209 314 PNKAKT-EMKELRLLCAEDEQIRTCWMTAFRLLKYGMLLYQNYR 356
Cdd:cd01259   81 PNKQQEkGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124
RA_GRB10 cd16141
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, ...
114-205 9.28e-60

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, also termed insulin receptor-binding protein Grb-IR, is a multi-domain cytoplasmic adaptor protein that binds to the insulin-like growth factor 1 receptor (IGF-1R) and inhibits insulin signaling. Grb10 and its related family members Grb7 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb14 binds to both GTPase-defective mutant Rab5 as well as CNGA1, whereas Grb10 binds only to GTP-bound form of active Rab5.


:

Pssm-ID: 340558  Cd Length: 92  Bit Score: 192.39  E-value: 9.28e-60
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 114 AKHDVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMPSESKFLF 193
Cdd:cd16141    1 EKHIVKVFSEDGTSKVVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVQSTMGSESKFLF 80
                         90
                 ....*....|..
gi 294979209 194 RKNYAKYEFFKN 205
Cdd:cd16141   81 RKNYAKYEFFKN 92
BPS pfam08947
BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and ...
372-415 6.60e-20

BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and a C-terminal helix, is an approximately 45 residue region found in the adaptor proteins Grb7/10/14 that mediates inhibition of the tyrosine kinase domain of the insulin receptor by binding of the N-terminal portion of the BPS domain to the substrate peptide groove of the kinase, acting as a pseudosubstrate inhibitor.


:

Pssm-ID: 462644  Cd Length: 46  Bit Score: 83.02  E-value: 6.60e-20
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 294979209  372 RSVSENSLVAMDFSGQIGRVIDNPAEAQSAALEEGHAWRKRSTR 415
Cdd:pfam08947   1 RSVSESSLVAMDFSGAGGRVIENPEEALSEAEEEGAAWRKKTLR 44
 
Name Accession Description Interval E-value
SH2_Grb10 cd10415
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) ...
434-541 1.66e-70

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb10 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198278  Cd Length: 108  Bit Score: 221.05  E-value: 1.66e-70
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd10415    1 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFSLDDGNTKFSD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd10415   81 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 108
PH_APBB1IP cd01259
Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin ...
234-356 1.49e-62

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.


Pssm-ID: 269961  Cd Length: 124  Bit Score: 200.93  E-value: 1.49e-62
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 234 NTSSCPEIQGFLQVKEVGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIFYLIAGKKQYNAPNEHGMCIK 313
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80
                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 294979209 314 PNKAKT-EMKELRLLCAEDEQIRTCWMTAFRLLKYGMLLYQNYR 356
Cdd:cd01259   81 PNKQQEkGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124
RA_GRB10 cd16141
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, ...
114-205 9.28e-60

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, also termed insulin receptor-binding protein Grb-IR, is a multi-domain cytoplasmic adaptor protein that binds to the insulin-like growth factor 1 receptor (IGF-1R) and inhibits insulin signaling. Grb10 and its related family members Grb7 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb14 binds to both GTPase-defective mutant Rab5 as well as CNGA1, whereas Grb10 binds only to GTP-bound form of active Rab5.


Pssm-ID: 340558  Cd Length: 92  Bit Score: 192.39  E-value: 9.28e-60
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 114 AKHDVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMPSESKFLF 193
Cdd:cd16141    1 EKHIVKVFSEDGTSKVVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVQSTMGSESKFLF 80
                         90
                 ....*....|..
gi 294979209 194 RKNYAKYEFFKN 205
Cdd:cd16141   81 RKNYAKYEFFKN 92
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
438-527 4.69e-25

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 98.84  E-value: 4.69e-25
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   438 QHWFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGqtfFTLdDGNTKFSDLIQL 517
Cdd:smart00252   1 QPWYHGFISREEAEKLLKNEG--DGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRNEDGK---FYL-EGGRKFPSLVEL 74
                           90
                   ....*....|
gi 294979209   518 VDFYQLNKGV 527
Cdd:smart00252  75 VEHYQKNSLG 84
BPS pfam08947
BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and ...
372-415 6.60e-20

BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and a C-terminal helix, is an approximately 45 residue region found in the adaptor proteins Grb7/10/14 that mediates inhibition of the tyrosine kinase domain of the insulin receptor by binding of the N-terminal portion of the BPS domain to the substrate peptide groove of the kinase, acting as a pseudosubstrate inhibitor.


Pssm-ID: 462644  Cd Length: 46  Bit Score: 83.02  E-value: 6.60e-20
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 294979209  372 RSVSENSLVAMDFSGQIGRVIDNPAEAQSAALEEGHAWRKRSTR 415
Cdd:pfam08947   1 RSVSESSLVAMDFSGAGGRVIENPEEALSEAEEEGAAWRKKTLR 44
SH2 pfam00017
SH2 domain;
440-521 2.11e-18

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 79.57  E-value: 2.11e-18
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpCEDDGQTFFTlddGNTKFSDLIQLVD 519
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGK-PDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQ-STDNGGYYIS---GGVKFSSLAELVE 75

                  ..
gi 294979209  520 FY 521
Cdd:pfam00017  76 HY 77
RA smart00314
Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); ...
114-197 5.39e-16

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)


Pssm-ID: 214612  Cd Length: 90  Bit Score: 73.10  E-value: 5.39e-16
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   114 AKHDVKVFSED---GTSKVVEILTDMTARDLCQLLVYKSHCVDD-NSWTLVEHHPQlGLERCLEDHEIVVQVESTMPSE- 188
Cdd:smart00314   1 DTFVLRVYVDDlpgGTYKTLRVSSRTTARDVIQQLLEKFHLTDDpEEYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRg 79
                           90
                   ....*....|.
gi 294979209   189 --SKFLFRKNY 197
Cdd:smart00314  80 pnLRFVLRKRD 90
RA pfam00788
Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); ...
114-198 6.23e-13

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.


Pssm-ID: 425871  Cd Length: 93  Bit Score: 64.66  E-value: 6.23e-13
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  114 AKHDVKVFSEDG----TSKVVEILTDMTARDLCQLLVYKSHCVDD-NSWTLVEHHPQLGLERCLEDHEIVVQVES---TM 185
Cdd:pfam00788   1 DDGVLKVYTEDGkpgtTYKTILVSSSTTAEEVIEALLEKFGLEDDpRDYVLVEVLERGGGERRLPDDECPLQIQLqwpRD 80
                          90
                  ....*....|...
gi 294979209  186 PSESKFLFRKNYA 198
Cdd:pfam00788  81 ASDSRFLLRKRDD 93
PH smart00233
Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The ...
239-347 1.12e-11

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.


Pssm-ID: 214574 [Multi-domain]  Cd Length: 102  Bit Score: 61.41  E-value: 1.12e-11
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   239 PEIQGFLQVKE-VGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIfylIAGKKQYNAPNEHGMCIkpnka 317
Cdd:smart00233   1 VIKEGWLYKKSgGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTV---REAPDPDSSKKPHCFEI----- 72
                           90       100       110
                   ....*....|....*....|....*....|
gi 294979209   318 KTEMKELRLLCAEDEQIRTCWMTAFRLLKY 347
Cdd:smart00233  73 KTSDRKTLLLQAESEEEREKWVEALRKAIA 102
PH pfam00169
PH domain; PH stands for pleckstrin homology.
239-347 8.59e-10

PH domain; PH stands for pleckstrin homology.


Pssm-ID: 459697 [Multi-domain]  Cd Length: 105  Bit Score: 56.03  E-value: 8.59e-10
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  239 PEIQGFLQVKE-VGRKSWKKLYVCLRRSGLYY---STKGTSKEPRHLQLLADLEESSIfyliagKKQYNAPNEHGMCIKP 314
Cdd:pfam00169   1 VVKEGWLLKKGgGKKKSWKKRYFVLFDGSLLYykdDKSGKSKEPKGSISLSGCEVVEV------VASDSPKRKFCFELRT 74
                          90       100       110
                  ....*....|....*....|....*....|...
gi 294979209  315 NKAKTemKELRLLCAEDEQIRTCWMTAFRLLKY 347
Cdd:pfam00169  75 GERTG--KRTYLLQAESEEERKDWIKAIQSAIR 105
 
Name Accession Description Interval E-value
SH2_Grb10 cd10415
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) ...
434-541 1.66e-70

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb10 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198278  Cd Length: 108  Bit Score: 221.05  E-value: 1.66e-70
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd10415    1 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFSLDDGNTKFSD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd10415   81 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 108
SH2_Grb7_family cd09944
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) ...
434-541 8.29e-69

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. There are 3 members of the Grb7 family of proteins: Grb7, Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR). Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198197 [Multi-domain]  Cd Length: 108  Bit Score: 216.52  E-value: 8.29e-69
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd09944    1 IHRSQPWFHGGISRDEAARLIRQQGLVDGVFLVRESQSNPGAFVLSLKHGQKIKHYQIIPIEDEGQWYFTLDDGVTKFYD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd09944   81 LLQLVEFYQLNAGSLPTRLKHYCTRVAL 108
PH_APBB1IP cd01259
Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin ...
234-356 1.49e-62

Amyloid beta (A4) Precursor protein-Binding, family B, member 1 Interacting Protein pleckstrin homology (PH) domain; APBB1IP consists of a Ras-associated (RA) domain, a PH domain, a family-specific BPS region, and a C-terminal SH2 domain. Grb7, Grb10 and Grb14 are paralogs that are also present in this hierarchy. These adapter proteins bind a variety of receptor tyrosine kinases, including the insulin and insulin-like growth factor-1 (IGF1) receptors. Grb10 and Grb14 are important tissue-specific negative regulators of insulin and IGF1 signaling based and may contribute to type 2 (non-insulin-dependent) diabetes in humans. RA-PH function as a single structural unit and is dimerized via a helical extension of the PH domain. The PH domain here are proposed to bind phosphoinositides non-cannonically ahd are unlikely to bind an activated GTPase. The tandem RA-PH domains are present in a second adapter-protein family, MRL proteins, Caenorhabditis elegans protein MIG-1012, the mammalian proteins RIAM and lamellipodin and the Drosophila melanogaster protein Pico12, all of which are Ena/VASP-binding proteins involved in actin-cytoskeleton rearrangement. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.


Pssm-ID: 269961  Cd Length: 124  Bit Score: 200.93  E-value: 1.49e-62
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 234 NTSSCPEIQGFLQVKEVGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIFYLIAGKKQYNAPNEHGMCIK 313
Cdd:cd01259    1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSKESRDLQCLAQFDDYNVYTGLNGKKKYKAPTDFGFCLK 80
                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 294979209 314 PNKAKT-EMKELRLLCAEDEQIRTCWMTAFRLLKYGMLLYQNYR 356
Cdd:cd01259   81 PNKQQEkGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124
RA_GRB10 cd16141
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, ...
114-205 9.28e-60

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 10; GRB10, also termed insulin receptor-binding protein Grb-IR, is a multi-domain cytoplasmic adaptor protein that binds to the insulin-like growth factor 1 receptor (IGF-1R) and inhibits insulin signaling. Grb10 and its related family members Grb7 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb14 binds to both GTPase-defective mutant Rab5 as well as CNGA1, whereas Grb10 binds only to GTP-bound form of active Rab5.


Pssm-ID: 340558  Cd Length: 92  Bit Score: 192.39  E-value: 9.28e-60
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 114 AKHDVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMPSESKFLF 193
Cdd:cd16141    1 EKHIVKVFSEDGTSKVVEILADMTARDLCQLLVYKSHCVDDNSWTLVEHHPHLGLERCLEDHELVVQVQSTMGSESKFLF 80
                         90
                 ....*....|..
gi 294979209 194 RKNYAKYEFFKN 205
Cdd:cd16141   81 RKNYAKYEFFKN 92
SH2_Grb14 cd10414
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) ...
434-541 1.10e-59

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb14 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR) and weakly to the erbB2 receptor. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198277  Cd Length: 108  Bit Score: 192.84  E-value: 1.10e-59
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd10414    1 IHRSQPWFHHKISRDEAQRLIIQQGLVDGVFLVRDSQSNPRTFVLSMSHGQKIKHFQIIPVEDDGELFHTLDDGHTRFTD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd10414   81 LIQLVEFYQLNKGVLPCKLKHYCARIAL 108
SH2_Grb7 cd10413
Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) ...
434-541 2.24e-56

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb7 is part of the Grb7 family of proteins which also includes Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198276  Cd Length: 108  Bit Score: 184.34  E-value: 2.24e-56
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 434 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSD 513
Cdd:cd10413    1 IHRTQPWFHGRISREESQRLIGQQGLVDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 80
                         90       100
                 ....*....|....*....|....*...
gi 294979209 514 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 541
Cdd:cd10413   81 LLQLVEFHQLNRGILPCLLRHCCTRVAL 108
RA_GRB7_10_14 cd16124
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 7/10/14; The ...
115-197 1.20e-46

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 7/10/14; The RA domain is highly conserved among the members of the Grb proteins family which includes Grb7, Grb10 and Grb14. Grb7/10/14 are multi-domain cytoplasmic adaptor proteins that are recruited to activated receptor tyrosine kinases. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. Grb7 and its related family members Grb10 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm.


Pssm-ID: 340541  Cd Length: 85  Bit Score: 157.79  E-value: 1.20e-46
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 115 KHDVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMPS--ESKFL 192
Cdd:cd16124    1 KQVVKVYSEDGTSRSVEVAADATARDVCQLLVQKAHALDDESWTLVEHHPHLGLERGLEDHELVVEVQSAWPVggESKFV 80

                 ....*
gi 294979209 193 FRKNY 197
Cdd:cd16124   81 FRKNY 85
RA_GRB7 cd16140
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 7; GRB7, also ...
116-199 8.02e-37

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 7; GRB7, also termed B47, or epidermal growth factor receptor GRB-7, or GRB7 adapter protein, is a signal-transducing cytoplasmic adaptor protein that is co-opted by numerous tyrosine kinases involved in various cellular signaling and functions. Grb7 and its related family members Grb10 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm. Grb7 could interact with activated N-Ras in transfected cells.


Pssm-ID: 340557  Cd Length: 88  Bit Score: 131.51  E-value: 8.02e-37
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 116 HDVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMP--SESKFLF 193
Cdd:cd16140    3 HVVKVYSEDGTCRSLEVTAGATARHVCEMLVQRAHCLDDESWSLVELHPHLALERCLEDHESVVEVQATWPagGDSRFVF 82

                 ....*.
gi 294979209 194 RKNYAK 199
Cdd:cd16140   83 RKNFAK 88
RA_MRL_like cd17112
Ras-associating (RA) domain found in Mig10/RIAM/Lpd (MRL) family and growth factor ...
117-195 1.31e-35

Ras-associating (RA) domain found in Mig10/RIAM/Lpd (MRL) family and growth factor receptor-bound (Grb) protein 7/10/14; MRL proteins share a common structural architecture, including a central structural unit consisting of a Ras-associating (RA) domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain. MRL proteins have distinct functions in cell migration and adhesion, signaling, and in cell growth. Grb7/10/14 are multi-domain cytoplasmic adaptor proteins that are recruited to activated receptor tyrosine kinases. Grb7 and its related family members Grb10 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and pleckstrin homology (PH) domains, and a carboxyl-terminal SH2 domain. The tandem RA and PH domains of Grb7/10/14 are also found in a second adaptor family, Rap1-interacting adaptor molecule (RIAM) and lamellipodin, which is involved in actin-cytoskeleton rearrangement. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm.


Pssm-ID: 340632  Cd Length: 81  Bit Score: 127.78  E-value: 1.31e-35
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 117 DVKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVESTMP--SESKFLFR 194
Cdd:cd17112    1 VVKVYNEDGSSKTVAVDENMTARDVCQILVEKNHVDPDKSWSLVEELPELGLERTLEDHELVVDVYSKWPsdSNNKFLFR 80

                 .
gi 294979209 195 K 195
Cdd:cd17112   81 K 81
RA_GRB14 cd16139
Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 14; Grb14, a ...
118-197 1.47e-33

Ras-associating (RA) domain found in growth factor receptor-bound (Grb) protein 14; Grb14, a member of cytoplasmic adaptor proteins, is a tissue-specific negative regulator of insulin signaling. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ubi is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. A novel function of Grb14 RA domain is to interact with the nucleotide binding pocket of a cyclic nucleotide gated channel alpha subunit (CNGA1) and inhibits its activity. Grb7 and its related family members Grb10 and Grb14 share a conserved domain architecture that includes an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes the RA, PIR, and PH domains, and a carboxyl-terminal SH2 domain. Grb7/10/14 family proteins are phosphorylated on serine/threonine as well as tyrosine residues and are mainly localized to the cytoplasm.


Pssm-ID: 340556  Cd Length: 85  Bit Score: 122.25  E-value: 1.47e-33
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVEST--MPSESKFLFRK 195
Cdd:cd16139    4 IKVYSEDDTSRALEVPNDITARDVCQLFILKNHYIDDHSWTLFEHLPHIGLERIIEDHESVIEVQSNwgMETDSRLYFRK 83

                 ..
gi 294979209 196 NY 197
Cdd:cd16139   84 NY 85
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
438-527 4.69e-25

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 98.84  E-value: 4.69e-25
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   438 QHWFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGqtfFTLdDGNTKFSDLIQL 517
Cdd:smart00252   1 QPWYHGFISREEAEKLLKNEG--DGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRNEDGK---FYL-EGGRKFPSLVEL 74
                           90
                   ....*....|
gi 294979209   518 VDFYQLNKGV 527
Cdd:smart00252  75 VEHYQKNSLG 84
BPS pfam08947
BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and ...
372-415 6.60e-20

BPS (Between PH and SH2); The BPS (Between PH and SH2) domain, comprised of 2 beta strands and a C-terminal helix, is an approximately 45 residue region found in the adaptor proteins Grb7/10/14 that mediates inhibition of the tyrosine kinase domain of the insulin receptor by binding of the N-terminal portion of the BPS domain to the substrate peptide groove of the kinase, acting as a pseudosubstrate inhibitor.


Pssm-ID: 462644  Cd Length: 46  Bit Score: 83.02  E-value: 6.60e-20
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 294979209  372 RSVSENSLVAMDFSGQIGRVIDNPAEAQSAALEEGHAWRKRSTR 415
Cdd:pfam08947   1 RSVSESSLVAMDFSGAGGRVIENPEEALSEAEEEGAAWRKKTLR 44
SH2 cd00173
Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they ...
440-521 1.94e-18

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.


Pssm-ID: 198173 [Multi-domain]  Cd Length: 79  Bit Score: 79.81  E-value: 1.94e-18
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQglVDGLFLLRDSQSNPKAFVLTLCHH-QKIKNFQIlpcEDDGQTFFTLDDGNTKFSDLIQLV 518
Cdd:cd00173    2 WFHGSISREEAERLLRGK--PDGTFLVRESSSEPGDYVLSVRSGdGKVKHYLI---ERNEGGYYLLGGSGRTFPSLPELV 76

                 ...
gi 294979209 519 DFY 521
Cdd:cd00173   77 EHY 79
SH2 pfam00017
SH2 domain;
440-521 2.11e-18

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 79.57  E-value: 2.11e-18
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpCEDDGQTFFTlddGNTKFSDLIQLVD 519
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGK-PDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQ-STDNGGYYIS---GGVKFSSLAELVE 75

                  ..
gi 294979209  520 FY 521
Cdd:pfam00017  76 HY 77
RA smart00314
Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); ...
114-197 5.39e-16

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Kalhammer et al. have shown that not all RA domains bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase. Predicted RA domains in PLC210 and nore1 found to bind RasGTP. Included outliers (Grb7, Grb14, adenylyl cyclases etc.)


Pssm-ID: 214612  Cd Length: 90  Bit Score: 73.10  E-value: 5.39e-16
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   114 AKHDVKVFSED---GTSKVVEILTDMTARDLCQLLVYKSHCVDD-NSWTLVEHHPQlGLERCLEDHEIVVQVESTMPSE- 188
Cdd:smart00314   1 DTFVLRVYVDDlpgGTYKTLRVSSRTTARDVIQQLLEKFHLTDDpEEYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRg 79
                           90
                   ....*....|.
gi 294979209   189 --SKFLFRKNY 197
Cdd:smart00314  80 pnLRFVLRKRD 90
RA_MRL cd01787
Ras-associating (RA) domain of Mig10/RIAM/Lpd (MRL) family; MRL proteins share a common ...
118-193 2.71e-15

Ras-associating (RA) domain of Mig10/RIAM/Lpd (MRL) family; MRL proteins share a common structural architecture, including a central structural unit consisting of a Ras-associating (RA) domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain. MRL proteins have distinct functions in cell migration and adhesion, signaling, and in cell growth.


Pssm-ID: 340485  Cd Length: 85  Bit Score: 70.91  E-value: 2.71e-15
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVES--TMPSESKFLF 193
Cdd:cd01787    4 VKVHMEDGSSKTLLVDERMTVRQVLKQLIEKNHCDPSVDWCLVEQYPDLYMERVFEDHEKLVENLLnwTRDSTNKLLF 81
SH2_Cterm_shark_like cd10348
C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...
439-521 2.74e-15

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in its carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198211  Cd Length: 86  Bit Score: 70.91  E-value: 2.74e-15
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 439 HWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpCEDDgqTFFTLDDGnTKFSDLIQLV 518
Cdd:cd10348    1 QWLHGALDRNEAVEILKQKADADGSFLVRYSRRRPGGYVLTLVYENHVYHFEIQ-NRDD--KWFYIDDG-PYFESLEHLI 76

                 ...
gi 294979209 519 DFY 521
Cdd:cd10348   77 EHY 79
SH2_csk_like cd09937
Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal ...
440-533 2.99e-15

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are members of the CSK-family of protein tyrosine kinases. These proteins suppress activity of Src-family kinases (SFK) by selectively phosphorylating the conserved C-terminal tail regulatory tyrosine by a similar mechanism. CHK is also capable of inhibiting SFKs by a non-catalytic mechanism that involves binding of CHK to SFKs to form stable protein complexes. The unphosphorylated form of SFKs is inhibited by CSK and CHK by a two-step mechanism. The first step involves the formation of a complex of SFKs with CSK/CHK with the SFKs in the complex are inactive. The second step, involves the phosphorylation of the C-terminal tail tyrosine of SFKs, which then dissociates and adopt an inactive conformation. The structural basis of how the phosphorylated SFKs dissociate from CSK/CHK to adopt the inactive conformation is not known. The inactive conformation of SFKs is stabilized by two intramolecular inhibitory interactions: (a) the pYT:SH2 interaction in which the phosphorylated C-terminal tail tyrosine (YT) binds to the SH2 domain, and (b) the linker:SH3 interaction of which the SH2-kinase domain linker binds to the SH3 domain. SFKs are activated by multiple mechanisms including binding of the ligands to the SH2 and SH3 domains to displace the two inhibitory intramolecular interactions, autophosphorylation, and dephosphorylation of YT. By selective phosphorylation and the non-catalytic inhibitory mechanism CSK and CHK are able to inhibit the active forms of SFKs. CSK and CHK are regulated by phosphorylation and inter-domain interactions. They both contain SH3, SH2, and kinase domains separated by the SH3-SH2 connector and SH2 kinase linker, intervening segments separating the three domains. They lack a conserved tyrosine phosphorylation site in the kinase domain and the C-terminal tail regulatory tyrosine phosphorylation site. The CSK SH2 domain is crucial for stabilizing the kinase domain in the active conformation. A disulfide bond here regulates CSK kinase activity. The subcellular localization and activity of CSK are regulated by its SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198190  Cd Length: 98  Bit Score: 71.55  E-value: 2.99e-15
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpcEDDGQtfFTLDDGNTkFSDLIQLVD 519
Cdd:cd09937    5 WFHGKISREEAERLLQPPE--DGLFLVRESTNYPGDYTLCVSFEGKVEHYRVI--YRNGK--LTIDEEEY-FENLIQLVE 77
                         90
                 ....*....|....
gi 294979209 520 FYQLNKGVLPCKLK 533
Cdd:cd09937   78 HYTKDADGLCTRLV 91
SH2_Nterm_shark_like cd10347
N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...
438-521 9.39e-15

N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in the carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198210  Cd Length: 81  Bit Score: 69.33  E-value: 9.39e-15
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpcEDDGQTFFTLDDGNTKFSDLIQL 517
Cdd:cd10347    1 LRWYHGKISREVAEALLLREGGRDGLFLVRESTSAPGDYVLSLLAQGEVLHYQI---RRHGEDAFFSDDGPLIFHGLDTL 77

                 ....
gi 294979209 518 VDFY 521
Cdd:cd10347   78 IEHY 81
SH2_N-SH2_Zap70_Syk_like cd09938
N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...
440-538 1.21e-13

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the N-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198191  Cd Length: 104  Bit Score: 67.03  E-value: 1.21e-13
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpcEDDGQTFFTLDDGNtKFSDLIQLVD 519
Cdd:cd09938    3 FFYGSITREEAEEYLKLAGMSDGLFLLRQSLRSLGGYVLSVCHGRKFHHYTI---ERQLNGTYAIAGGK-AHCGPAELCE 78
                         90
                 ....*....|....*....
gi 294979209 520 FYQLNKGVLPCKLKHHCIR 538
Cdd:cd09938   79 YHSTDLDGLVCLLRKPCNR 97
SH2_C-SH2_PLC_gamma_like cd09932
C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...
435-534 5.47e-13

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198186  Cd Length: 104  Bit Score: 64.98  E-value: 5.47e-13
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 435 HRTQHWFHGRISREESHRIIKQQGLvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpcEDDGQTFFTlddGNTKFSDL 514
Cdd:cd09932    1 HESKEWFHANLTREQAEEMLMRVPR-DGAFLVRPSETDPNSFAISFRAEGKIKHCRI---KQEGRLFVI---GTSQFESL 73
                         90       100
                 ....*....|....*....|
gi 294979209 515 IQLVDFYQLNKGVLPCKLKH 534
Cdd:cd09932   74 VELVSYYEKHPLYRKIKLRY 93
RA pfam00788
Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); ...
114-198 6.23e-13

Ras association (RalGDS/AF-6) domain; RasGTP effectors (in cases of AF6, canoe and RalGDS); putative RasGTP effectors in other cases. Recent evidence (not yet in MEDLINE) shows that some RA domains do NOT bind RasGTP. Predicted structure similar to that determined, and that of the RasGTP-binding domain of Raf kinase.


Pssm-ID: 425871  Cd Length: 93  Bit Score: 64.66  E-value: 6.23e-13
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  114 AKHDVKVFSEDG----TSKVVEILTDMTARDLCQLLVYKSHCVDD-NSWTLVEHHPQLGLERCLEDHEIVVQVES---TM 185
Cdd:pfam00788   1 DDGVLKVYTEDGkpgtTYKTILVSSSTTAEEVIEALLEKFGLEDDpRDYVLVEVLERGGGERRLPDDECPLQIQLqwpRD 80
                          90
                  ....*....|...
gi 294979209  186 PSESKFLFRKNYA 198
Cdd:pfam00788  81 ASDSRFLLRKRDD 93
SH2_Grb2_like cd09941
Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar ...
439-522 1.07e-12

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar proteins; The adaptor proteins here include homologs Grb2 in humans, Sex muscle abnormal protein 5 (Sem-5) in Caenorhabditis elegans, and Downstream of receptor kinase (drk) in Drosophila melanogaster. They are composed of one SH2 and two SH3 domains. Grb2/Sem-5/drk regulates the Ras pathway by linking the tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state. The SH2 domain of Grb2/Sem-5/drk binds class II phosphotyrosyl peptides while its SH3 domain binds to Sos and Sos-derived, proline-rich peptides. Besides it function in Ras signaling, Grb2 is also thought to play a role in apoptosis. Unlike most SH2 structures in which the peptide binds in an extended conformation (such that the +3 peptide residue occupies a hydrophobic pocket in the protein, conferring a modest degree of selectivity), Grb2 forms several hydrogen bonds via main chain atoms with the side chain of +2 Asn. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199828  Cd Length: 95  Bit Score: 63.83  E-value: 1.07e-12
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 439 HWFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpcEDDGQTFFTLDdgnTKFSDLIQLV 518
Cdd:cd09941    4 PWFHGKISRAEAEEILMNQR-PDGAFLIRESESSPGDFSLSVKFGNDVQHFKVL--RDGAGKYFLWV---VKFNSLNELV 77

                 ....
gi 294979209 519 DFYQ 522
Cdd:cd09941   78 DYHR 81
SH2_Src_family cd09933
Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src ...
437-532 6.04e-12

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src family kinases are nonreceptor tyrosine kinases that have been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. It is thought that transforming ability of Src is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. As such blocking Src activation has been a target for drug companies. Src family members can be divided into 3 groups based on their expression pattern: 1) Src, Fyn, and Yes; 2) Blk, Fgr, Hck, Lck, and Lyn; and 3) Frk-related kinases Frk/Rak and Iyk/Bsk Of these, cellular c-Src is the best studied and most frequently implicated in oncogenesis. The c-Src contains five distinct regions: a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Src exists in both active and inactive conformations. Negative regulation occurs through phosphorylation of Tyr, resulting in an intramolecular association between phosphorylated Tyr and the SH2 domain of SRC, which locks the protein in a closed conformation. Further stabilization of the inactive state occurs through interactions between the SH3 domain and a proline-rich stretch of residues within the kinase domain. Conversely, dephosphorylation of Tyr allows SRC to assume an open conformation. Full activity requires additional autophosphorylation of a Tyr residue within the catalytic domain. Loss of the negative-regulatory C-terminal segment has been shown to result in increased activity and transforming potential. Phosphorylation of the C-terminal Tyr residue by C-terminal Src kinase (Csk) and Csk homology kinase results in increased intramolecular interactions and consequent Src inactivation. Specific phosphatases, protein tyrosine phosphatase a (PTPa) and the SH-containing phosphatases SHP1/SHP2, have also been shown to take a part in Src activation. Src is also activated by direct binding of focal adhesion kinase (Fak) and Crk-associated substrate (Cas) to the SH2 domain. SRC activity can also be regulated by numerous receptor tyrosine kinases (RTKs), such as Her2, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199827  Cd Length: 101  Bit Score: 62.21  E-value: 6.04e-12
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTL----------CHHQKIKNFqilpceDDGQTFFTldd 506
Cdd:cd09933    2 AEEWFFGKIKRKDAEKLLLAPGNPRGTFLIRESETTPGAYSLSVrdgddargdtVKHYRIRKL------DNGGYYIT--- 72
                         90       100
                 ....*....|....*....|....*.
gi 294979209 507 GNTKFSDLIQLVDFYQLNKGVLPCKL 532
Cdd:cd09933   73 TRATFPTLQELVQHYSKDADGLCCRL 98
RA_MRL_MIG10 cd16138
Ras-associating (RA) domain found in Caenorhabditis elegans abnormal cell migration protein 10 ...
118-193 8.95e-12

Ras-associating (RA) domain found in Caenorhabditis elegans abnormal cell migration protein 10 (MIG-10) and similar proteins; MIG-10 is lamellipodin (Lpd) found in C. elegans. It stabilizes invading cell adhesion to basement membrane and is a negative transcriptional target of Evi-1 proto-oncogene, EGL-43, in C. elegans. It also shows netrin-independent functions and is a transcriptional target of FOS-1A, a transcription factor that promotes basement membrane breaching, during anchor cell invasion in C. elegans. MIG-10 is a member of MRL (Mig10/RIAM/Lpd) family of proteins that is involved in antero-posterior migration of embryonic neurons CAN (canalassociated neurons), ALM (anterior lateral microtubule cells) and HSN (hermaphrodite-specific neurons). MRL proteins share a common structural architecture, including a central structural unit consisting of an RA domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain.


Pssm-ID: 340555  Cd Length: 86  Bit Score: 60.93  E-value: 8.95e-12
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQ--VESTMPSESKFLF 193
Cdd:cd16138    5 VKAFTEDGSAKSLLVDERMTVGHVTRLLADKNHVAMMPDWAIVEHIPDLYMERVYEDHEKLVEnlMMWTRDSPNRLLF 82
PH smart00233
Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The ...
239-347 1.12e-11

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.


Pssm-ID: 214574 [Multi-domain]  Cd Length: 102  Bit Score: 61.41  E-value: 1.12e-11
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   239 PEIQGFLQVKE-VGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIfylIAGKKQYNAPNEHGMCIkpnka 317
Cdd:smart00233   1 VIKEGWLYKKSgGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTV---REAPDPDSSKKPHCFEI----- 72
                           90       100       110
                   ....*....|....*....|....*....|
gi 294979209   318 KTEMKELRLLCAEDEQIRTCWMTAFRLLKY 347
Cdd:smart00233  73 KTSDRKTLLLQAESEEEREKWVEALRKAIA 102
SH2_C-SH2_SHP_like cd09931
C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...
440-524 2.52e-11

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198185  Cd Length: 99  Bit Score: 60.37  E-value: 2.52e-11
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLT-LCHHQKIKNFQILpCEDDGQTFftldDGNTKFSDLIQLV 518
Cdd:cd09931    2 WFHGHLSGKEAEKLLLEKG-KPGSFLVRESQSKPGDFVLSvRTDDDKVTHIMIR-CQGGKYDV----GGGEEFDSLTDLV 75

                 ....*.
gi 294979209 519 DFYQLN 524
Cdd:cd09931   76 EHYKKN 81
RA_MRL_RIAM cd16137
Ras-associating (RA) domain found in Rap1-GTP-interacting adapter molecule (RIAM); RIAM, also ...
118-200 7.23e-11

Ras-associating (RA) domain found in Rap1-GTP-interacting adapter molecule (RIAM); RIAM, also termed amyloid beta A4 precursor protein-binding family B member 1-interacting protein, or APBB1-interacting protein 1, or proline-rich EVH1 ligand 1 (PREL-1), or proline-rich protein 73, or retinoic acid-responsive proline-rich protein 1 (RARP-1), is a member of MRL (Mig10/RIAM/Lpd) family proteins that regulates cell migration and promote lamellipodia protrusion in fibroblast by interacting with Ena/VASP proteins. RIAM regulates cell migration and mediates Rap1-induced cell adhesion. MRL proteins share a common structural architecture, including a central structural unit consisting of an RA domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RIAM also contains a helical region at the amino terminus for talin binding. RA and PH form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain.


Pssm-ID: 340554  Cd Length: 89  Bit Score: 58.73  E-value: 7.23e-11
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQVES--TMPSESKFLFRK 195
Cdd:cd16137    5 VKVHMNDSSTKTLMVDERQTVRDVLDNLFEKTHCDCNVDWCLYEVNPELQIERFFEDHENVVEVLSdwTRDSENKVLFLE 84

                 ....*
gi 294979209 196 NYAKY 200
Cdd:cd16137   85 KKEKY 89
SH2_N-SH2_SHP_like cd10340
N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...
440-528 8.15e-11

N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [IVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198203  Cd Length: 99  Bit Score: 58.95  E-value: 8.15e-11
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDdgqtFFTLDDGNtKFSDLIQLVD 519
Cdd:cd10340    2 WFHPVISGIEAENLLKTRG-VDGSFLARPSKSNPGDFTLSVRRGDEVTHIKIQNTGD----YYDLYGGE-KFATLSELVQ 75

                 ....*....
gi 294979209 520 FYQLNKGVL 528
Cdd:cd10340   76 YYMEQHGQL 84
SH2_Nck_family cd09943
Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate ...
438-522 1.23e-10

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198196  Cd Length: 93  Bit Score: 58.30  E-value: 1.23e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpceDDGQTFFTLddGNTKFSDLIQL 517
Cdd:cd09943    1 QPWYYGRITRHQAETLLNEHG-HEGDFLIRDSESNPGDYSVSLKAPGRNKHFKV----QVVDNVYCI--GQRKFHTMDEL 73

                 ....*
gi 294979209 518 VDFYQ 522
Cdd:cd09943   74 VEHYK 78
SH2_ABL cd09935
Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ...
440-534 2.77e-10

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198189  Cd Length: 94  Bit Score: 57.01  E-value: 2.77e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQqgLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlPCEDDGQTFFTLDdgnTKFSDLIQLVD 519
Cdd:cd09935    5 WYHGPISRNAAEYLLSS--GINGSFLVRESESSPGQYSISLRYDGRVYHYRI-SEDSDGKVYVTQE---HRFNTLAELVH 78
                         90
                 ....*....|....*
gi 294979209 520 FYQLNKGVLPCKLKH 534
Cdd:cd09935   79 HHSKNADGLITTLRY 93
SH2_N-SH2_PLC_gamma_like cd10341
N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...
435-525 4.25e-10

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199829  Cd Length: 99  Bit Score: 56.59  E-value: 4.25e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 435 HRTQHWFHGRIS--REESHRIIKQ-QGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDgNTKF 511
Cdd:cd10341    1 HFTEPWFHGKLGdgRDEAEKLLLEyCEGGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIRSRQENGEKKYYLTD-NLVF 79
                         90
                 ....*....|....
gi 294979209 512 SDLIQLVDFYQLNK 525
Cdd:cd10341   80 DSLYELIDYYRQNP 93
SH2_Fps_family cd10361
Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related ...
435-525 5.07e-10

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related (Fes/Fps/Fer) proteins; The Fps family consists of members Fps/Fes and Fer/Flk/Tyk3. They are cytoplasmic protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. Fes/Fps/Fer contains three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. Members here include: Fps/Fes, Fer, Kin-31, and In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198224  Cd Length: 90  Bit Score: 56.38  E-value: 5.07e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 435 HRTQHWFHGRISREESHRIIKQQGlvDglFLLRDSQ---SNPKAFVLTLCHHQKIKNFQIlPCEDDGQTFFTlddgNTKF 511
Cdd:cd10361    3 LENEPYYHGLLPREDAEELLKNDG--D--FLVRKTEpkgGGKRKLVLSVRWDGKIRHFVI-NRDDGGKYYIE----GKSF 73
                         90
                 ....*....|....
gi 294979209 512 SDLIQLVDFYQLNK 525
Cdd:cd10361   74 KSISELINYYQKTK 87
SH2_SHIP cd10343
Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and ...
438-534 6.39e-10

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and SLAM-associated protein (SAP); The SH2-containing inositol-5'-phosphatase, SHIP (also called SHIP1/SHIP1a), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, SHIP dampens down PIP3 mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. PIP3 recruits lipid-binding pleckstrin homology(PH) domain-containing proteins to the inner wall of the plasma membrane and activates them. PH domain-containing downstream effectors include the survival/proliferation enhancing serine/threonine kinase, Akt (protein kinase B), the tyrosine kinase, Btk, the regulator of protein translation, S6K, and the Rac and cdc42 guanine nucleotide exchange factor, Vav. SHIP is believed to act as a tumor suppressor during leukemogenesis and lymphomagenesis, and may play a role in activating the immune system to combat cancer. SHIP contains an N-terminal SH2 domain, a centrally located phosphatase domain that specifically hydrolyzes the 5'-phosphate from PIP3, PI-4,5-P2 and inositol-1,3,4,5- tetrakisphosphate (IP4), a C2 domain, that is an allosteric activating site when bound by SHIP's enzymatic product, PI-3,4-P2; 2 NPXY motifs that bind proteins with a phosphotyrosine binding (Shc, Dok 1, Dok 2) or an SH2 (p85a, SHIP2) domain; and a proline-rich domain consisting of four PxxP motifs that bind a subset of SH3-containing proteins including Grb2, Src, Lyn, Hck, Abl, PLCg1, and PIAS1. The SH2 domain of SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule, Cas, c-Cbl, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs). The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX(V/I), which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198206  Cd Length: 103  Bit Score: 56.30  E-value: 6.39e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTK-FSDLIQ 516
Cdd:cd10343    3 PPWYHGNITRSKAEELLSKAG-KDGSFLVRDSESVSGAYALCVLYQNCVHTYRILPNAEDKLSVQASEGVPVRfFTTLPE 81
                         90
                 ....*....|....*....
gi 294979209 517 LVDFY-QLNKGvLPCKLKH 534
Cdd:cd10343   82 LIEFYqKENMG-LVTHLLY 99
PH pfam00169
PH domain; PH stands for pleckstrin homology.
239-347 8.59e-10

PH domain; PH stands for pleckstrin homology.


Pssm-ID: 459697 [Multi-domain]  Cd Length: 105  Bit Score: 56.03  E-value: 8.59e-10
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209  239 PEIQGFLQVKE-VGRKSWKKLYVCLRRSGLYY---STKGTSKEPRHLQLLADLEESSIfyliagKKQYNAPNEHGMCIKP 314
Cdd:pfam00169   1 VVKEGWLLKKGgGKKKSWKKRYFVLFDGSLLYykdDKSGKSKEPKGSISLSGCEVVEV------VASDSPKRKFCFELRT 74
                          90       100       110
                  ....*....|....*....|....*....|...
gi 294979209  315 NKAKTemKELRLLCAEDEQIRTCWMTAFRLLKY 347
Cdd:pfam00169  75 GERTG--KRTYLLQAESEEERKDWIKAIQSAIR 105
SH2_CRK_like cd09926
Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the ...
440-523 9.28e-10

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198180 [Multi-domain]  Cd Length: 106  Bit Score: 55.94  E-value: 9.28e-10
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIkqQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQI--LPCEDDGQTFFTLddGNTKFSDLIQL 517
Cdd:cd09926    9 WYFGPMSRQEAQELL--QGQRHGVFLVRDSSTIPGDYVLSVSENSRVSHYIInsLGQPAPNQSRYRI--GDQEFDDLPAL 84

                 ....*.
gi 294979209 518 VDFYQL 523
Cdd:cd09926   85 LEFYKL 90
SH2_C-SH2_Zap70 cd10402
C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...
435-536 2.83e-09

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70); ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198265  Cd Length: 105  Bit Score: 54.54  E-value: 2.83e-09
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 435 HRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNpKAFVLTLCHHQKIKNFQILpceDDGQTFFTLDDGnTKFSDL 514
Cdd:cd10402    7 HERMPWYHGSIARDEAERRLYSGAQPDGKFLLRERKES-GTYALSLVYGKTVYHYRID---QDKSGKYSIPEG-TKFDTL 81
                         90       100
                 ....*....|....*....|..
gi 294979209 515 IQLVDFYQLNKGVLPCKLKHHC 536
Cdd:cd10402   82 WQLVEYLKLKPDGLIFVLRESC 103
SH2_C-SH2_Syk_like cd10401
C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 ...
440-521 4.29e-09

C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Syk. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198264  Cd Length: 99  Bit Score: 53.74  E-value: 4.29e-09
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGLVDGLFLLRDSQSNpKAFVLTLCHHQKIKNFQIlpcEDDGQTFFTLDDGNtKFSDLIQLVD 519
Cdd:cd10401    5 WFHGKISREESEQILLIGSKTNGKFLIRERDNN-GSYALCLLHDGKVLHYRI---DKDKTGKLSIPDGK-KFDTLWQLVE 79

                 ..
gi 294979209 520 FY 521
Cdd:cd10401   80 HY 81
SH2_SHC cd09925
Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide ...
436-479 2.66e-08

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide variety of pathways including regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. An adapter protein, SHC has been implicated in Ras activation following the stimulation of a number of different receptors, including growth factors [insulin, epidermal growth factor (EGF), nerve growth factor, and platelet derived growth factor (PDGF)], cytokines [interleukins 2, 3, and 5], erythropoietin, and granulocyte/macrophage colony-stimulating factor, and antigens [T-cell and B-cell receptors]. SHC has been shown to bind to tyrosine-phosphorylated receptors, and receptor stimulation leads to tyrosine phosphorylation of SHC. Upon phosphorylation, SHC interacts with another adapter protein, Grb2, which binds to the Ras GTP/GDP exchange factor mSOS which leads to Ras activation. SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198179  Cd Length: 104  Bit Score: 51.96  E-value: 2.66e-08
                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 294979209 436 RTQHWFHGRISREESHRIIKQqglvDGLFLLRDSQSNPKAFVLT 479
Cdd:cd09925    5 RGEPWYHGKMSRRDAESLLQT----DGDFLVRESTTTPGQYVLT 44
SH2_Cterm_RasGAP cd10354
C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...
440-506 2.94e-08

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the C-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198217  Cd Length: 77  Bit Score: 50.88  E-value: 2.94e-08
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDD-----GQTFFTLDD 506
Cdd:cd10354    2 WFHGKISREEAYNMLVKVG-GPGSFLVRESDNTPGDYSLSFRVNEGIKHFKIIPTGNNqfmmgGRYFSSLDD 72
SH2_a2chimerin_b2chimerin cd10352
Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins ...
441-518 6.33e-08

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins are a family of phorbol ester- and diacylglycerol-responsive GTPase-activating proteins. Alpha1-chimerin (formerly known as n-chimerin) and alpha2-chimerin are alternatively spliced products of a single gene, as are beta1- and beta2-chimerin. alpha1- and beta1-chimerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas alpha2- and beta2-chimerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors. All of the isoforms contain a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. Other C1 domain-containing diacylglycerol receptors including: PKC, Munc-13 proteins, phorbol ester binding scaffolding proteins involved in Ca2+-stimulated exocytosis, and RasGRPs, diacylglycerol-activated guanine-nucleotide exchange factors (GEFs) for Ras and Rap1. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198215  Cd Length: 91  Bit Score: 50.44  E-value: 6.33e-08
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 294979209 441 FHGRISREESHRIIKqqGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpceDDGQTFFtLDDGNTKFSDLIQLV 518
Cdd:cd10352    9 YHGLISREEAEQLLS--GASDGSYLIRESSRDDGYYTLSLRFNGKVKNYKLY---YDGKNHY-HYVGEKRFDTIHDLV 80
SH2_Nck1 cd10408
Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...
440-522 7.10e-08

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198271  Cd Length: 97  Bit Score: 50.41  E-value: 7.10e-08
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpCEDDgqTFFTLddGNTKFSDLIQLVD 519
Cdd:cd10408    3 WYYGKVTRHQAEMALNERG-NEGDFLIRDSESSPNDFSVSLKAQGKNKHFKV--QLKE--CVYCI--GQRKFSSMEELVE 75

                 ...
gi 294979209 520 FYQ 522
Cdd:cd10408   76 HYK 78
RA cd17043
Ras-associating (RA) domain, structurally similar to a beta-grasp ubiquitin-like fold; RA ...
118-195 9.27e-08

Ras-associating (RA) domain, structurally similar to a beta-grasp ubiquitin-like fold; RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in various functions ranging from tumor suppression to being oncoproteins. Ras proteins are small GTPases that are involved in cellular signal transduction. The RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes, including transcriptional regulation, cell cycle control, and DNA repair. RA-containing proteins include RalGDS, AF6, RIN, RASSF1, SNX27, CYR1, STE50, and phospholipase C epsilon.


Pssm-ID: 340563  Cd Length: 87  Bit Score: 49.62  E-value: 9.27e-08
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 118 VKVFSED----GTSKVVEILTDMTARDLCQLLVYKSHCVDDNS-WTLVEHHPQLGLERCLEDHEIVVQV---ESTMPSES 189
Cdd:cd17043    2 LKVYDDDlapgSAYKSILVSSTTTAREVVQLLLEKYGLEEDPEdYSLYEVSEKQETERVLHDDECPLLIqleWGPQGTEF 81

                 ....*.
gi 294979209 190 KFLFRK 195
Cdd:cd17043   82 RFVLKR 87
RA_MRL_Lpd cd16136
Ras-associating (RA) domain found in the adapter protein lamellipodin (Lpd); Lpd, also termed ...
118-199 1.22e-07

Ras-associating (RA) domain found in the adapter protein lamellipodin (Lpd); Lpd, also termed Ras-associated and pleckstrin homology domains-containing protein 1 (RAPH1), or amyotrophic lateral sclerosis 2 chromosomal region candidate gene 18 protein, or amyotrophic lateral sclerosis 2 chromosomal region candidate gene 9 protein, or proline-rich EVH1 ligand 2 (PREL-2), or protein RMO1, is a member of MRL (Mig10/RIAM/Lpd) family proteins that regulates cell migration and promote lamellipodia protrusion in fibroblast by interacting with Ena/VASP proteins. MRL proteins share a common structural architecture, including a central structural unit consisting of an RA domain and a pleckstrin homology (PH) domain, an upstream coiled-coil region, and a number of polyproline motifs. Lpd also contains a helical region at the amino terminus for talin binding. RA domain-containing proteins function by interacting with Ras proteins directly or indirectly and are involved in several different functions ranging from tumor suppression to being oncoproteins. RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub). Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes. RA and PH domain in Lpd form a tandem domain pair (RA-PH), and serve tightly coordinated functions in both Ras GTPase signaling via the RA domain and membrane translocalization via the PH domain. Lpd also exhibits other unique enzymatic functions including its catalytic activity of butyrylcholinesterase, a potent therapeutic treatment targeting cocaine abuse.


Pssm-ID: 340553  Cd Length: 90  Bit Score: 49.70  E-value: 1.22e-07
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLEDHEIVVQ--VESTMPSESKFLFRK 195
Cdd:cd16136    7 IRVHMSDDSSKTMMVDERQTVRQVLDNLMDKSHCGYSLDWSLVETISELQMERIFEDHENLVEnlLNWTRDSQNKLMFVE 86

                 ....
gi 294979209 196 NYAK 199
Cdd:cd16136   87 RIEK 90
SH2_BCAR3 cd10337
Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is ...
436-525 2.40e-06

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198200 [Multi-domain]  Cd Length: 136  Bit Score: 46.94  E-value: 2.40e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 436 RTQHWFHGRISREESHRIIKQqglvDGLFLLRDSQSNPKAFVLTlCH------HQKIKNFQILPCEDDGQTFFTLDDgnT 509
Cdd:cd10337    4 RSHAWYHGRIPRQVAESLVQR----EGDFLVRDSLSSPGDYVLT-CRwkgqplHFKINRVVLRPSEAYTRVQYQFED--E 76
                         90
                 ....*....|....*.
gi 294979209 510 KFSDLIQLVDFYQLNK 525
Cdd:cd10337   77 QFDSIPALVHFYVGNR 92
SH2_SH2B_family cd10346
Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein ...
440-490 3.35e-06

Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein family has 3 members: SH2B1 (SH2-B, PSM), SH2B2 (APS), and SH2B3 (Lnk). SH2B family members contain a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198209  Cd Length: 97  Bit Score: 45.49  E-value: 3.35e-06
                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 294979209 440 WFHGRISREESHRIIKQQGL-VDGLFLLRDSQSNPKAFVLTLchhqkikNFQ 490
Cdd:cd10346   10 WFHGTLSRSDAAQLVLHSGAdGHGVFLVRQSETRRGEFVLTF-------NFQ 54
SH2_Src_Src cd10365
Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src ...
436-522 3.41e-06

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src non-receptor type tyrosine kinase family of proteins. Src is thought to play a role in the regulation of embryonic development and cell growth. Members here include v-Src and c-Src. v-Src lacks the C-terminal inhibitory phosphorylation site and is therefore constitutively active as opposed to normal cellular src (c-Src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-Src is an oncogene whereas c-Src is a proto-oncogene. c-Src consists of three domains, an N-terminal SH3 domain, a central SH2 domain and a tyrosine kinase domain. The SH2 and SH3 domains work together in the auto-inhibition of the kinase domain. The phosphorylation of an inhibitory tyrosine near the c-terminus of the protein produces a binding site for the SH2 domain which then facilitates binding of the SH3 domain to a polyproline site within the linker between the SH2 domain and the kinase domain. Binding of the SH3 domain inactivates the enzyme. This allows for multiple mechanisms for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, or competitive binding of a polyproline binding site to the SH3 domain. Unlike most other Src members Src lacks cysteine residues in the SH4 domain that undergo palmitylation. Serine and threonine phosphorylation sites have also been identified in the unique domains of Src and are believed to modulate protein-protein interactions or regulate catalytic activity. Alternatively spliced forms of Src, which contain 6- or 11-amino acid insertions in the SH3 domain, are expressed in CNS neurons. c-Src has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198228  Cd Length: 101  Bit Score: 45.81  E-value: 3.41e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 436 RTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQ-----KIKNFQILPCeDDGQTFFTlddGNTK 510
Cdd:cd10365    1 QAEEWYFGKITRRESERLLLNAENPRGTFLVRESETTKGAYCLSVSDFDnakglNVKHYKIRKL-DSGGFYIT---SRTQ 76
                         90
                 ....*....|..
gi 294979209 511 FSDLIQLVDFYQ 522
Cdd:cd10365   77 FNSLQQLVAYYS 88
SH2_SAP1a cd10400
Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked ...
441-491 3.85e-06

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX[VI], which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198263  Cd Length: 103  Bit Score: 45.60  E-value: 3.85e-06
                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 294979209 441 FHGRISREESHRIIKQQGLvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQI 491
Cdd:cd10400    6 YHGKISRETGEKLLLAAGL-DGSYLLRDSESVPGVYCLCVLYKGYVYTYRV 55
PH cd00821
Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are ...
241-342 6.92e-06

Pleckstrin homology (PH) domain; PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.


Pssm-ID: 275388 [Multi-domain]  Cd Length: 92  Bit Score: 44.46  E-value: 6.92e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 241 IQGFLQVKE-VGRKSWKKLYVCLRRSGLYYSTKGTSKEPRHLQLLADLEESSIFYLIAGKKqynapnEHGMCIKPNKAKT 319
Cdd:cd00821    1 KEGYLLKRGgGGLKSWKKRWFVLFEGVLLYYKSKKDSSYKPKGSIPLSGILEVEEVSPKER------PHCFELVTPDGRT 74
                         90       100
                 ....*....|....*....|...
gi 294979209 320 emkelRLLCAEDEQIRTCWMTAF 342
Cdd:cd00821   75 -----YYLQADSEEERQEWLKAL 92
SH2_ShkD_ShkE cd10357
Src homology 2 (SH2) domain found in SH2 domain-bearing protein kinases D and E (ShkD and ShkE) ...
440-488 7.87e-06

Src homology 2 (SH2) domain found in SH2 domain-bearing protein kinases D and E (ShkD and ShkE); SH2-bearing genes cloned from Dictyostelium include two transcription factors, STATa and STATc, and a signaling factor, SHK1 (shkA). A database search of the Dictyostelium discoideum genome revealed two additional putative STAT sequences, dd-STATb and dd-STATd, and four additional putative SHK genes, dd-SHK2 (shkB), dd-SHK3 (shkC), dd-SHK4 (shkD), and dd-SHK5 (shkE). This model contains members of shkD and shkE. All of the SHK members are most closely related to the protein kinases found in plants. However these kinases in plants are not conjugated to any SH2 or SH2-like sequences. Alignment data indicates that the SHK SH2 domains carry some features of the STAT SH2 domains in Dictyostelium. When STATc's linker domain was used for a BLAST search, the sequence between the protein kinase domain and the SH2 domain (the linker) of SHK was recovered, suggesting a close relationship among these molecules within this region. SHK's linker domain is predicted to contain an alpha-helix which is indeed homologous to that of STAT. Based on the phylogenetic alignment, SH2 domains can be grouped into two categories, STAT-type and Src-type. SHK family members are in between, but are closer to the STAT-type which indicates a close relationship between SHK and STAT families in their SH2 domains and further supports the notion that SHKs linker-SH2 domain evolved from STAT or STATL (STAT-like Linker-SH2) domain found in plants. In SHK, STAT, and SPT6, the linker-SH2 domains all reside exclusively in the C-terminal regions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198220  Cd Length: 87  Bit Score: 44.42  E-value: 7.87e-06
                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 294979209 440 WFHGRISREESHRIIKqqGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKN 488
Cdd:cd10357   12 WFHGDISRDEAEKRLR--GRPEGTFLIRLSSTDPKKTPFTISKKKKSKP 58
SH2_Nck2 cd10409
Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...
440-522 8.68e-06

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198272  Cd Length: 98  Bit Score: 44.64  E-value: 8.68e-06
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlPCEDDGQTFftlddGNTKFSDLIQLVD 519
Cdd:cd10409    3 WYYGNVTRHQAECALNERG-VEGDFLIRDSESSPSDFSVSLKAVGKNKHFKV-QLVDNVYCI-----GQRRFNSMDELVE 75

                 ...
gi 294979209 520 FYQ 522
Cdd:cd10409   76 HYK 78
SH2_Tec_family cd09934
Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the ...
440-534 1.11e-05

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198188  Cd Length: 104  Bit Score: 44.31  E-value: 1.11e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSqSNPKAFVLTL----CHHQKIKNFQIlpCEDDGQTFFTLDdgNTKFSDLI 515
Cdd:cd09934    8 WYVGDMSRQRAESLLKQED-KEGCFVVRNS-STKGLYTVSLftkvPGSPHVKHYHI--KQNARSEFYLAE--KHCFETIP 81
                         90
                 ....*....|....*....
gi 294979209 516 QLVDFYQLNKGVLPCKLKH 534
Cdd:cd09934   82 ELINYHQHNSGGLATRLKY 100
SH2_nSH2_p85_like cd09942
N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are ...
436-524 1.29e-05

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198195  Cd Length: 110  Bit Score: 44.24  E-value: 1.29e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 436 RTQHWFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQIlpCEDDGQTFFTLDDgntKFSDLI 515
Cdd:cd09942    5 QEAEWYWGDISREEVNEKMRDTP--DGTFLVRDASTMKGDYTLTLRKGGNNKLIKI--FHRDGKYGFSDPL---TFNSVV 77

                 ....*....
gi 294979209 516 QLVDFYQLN 524
Cdd:cd09942   78 ELINYYRNN 86
SH2_Nterm_RasGAP cd10353
N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...
437-521 1.55e-05

N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general the longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the N-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198216  Cd Length: 103  Bit Score: 44.05  E-value: 1.55e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGLVdGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILP-CEDdgqtFFTlddGNTKFSDLI 515
Cdd:cd10353   18 TNQWYHGRLDRTIAEERLRQAGKL-GSYLIRESDRRPGSFVLSFLSRTGVNHFRIIAmCGD----YYI---GGRRFSSLS 89

                 ....*.
gi 294979209 516 QLVDFY 521
Cdd:cd10353   90 DLIGYY 95
SH2_C-SH2_Zap70_Syk_like cd10345
C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...
440-536 2.68e-05

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198208  Cd Length: 95  Bit Score: 43.14  E-value: 2.68e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGLVDGLFLLRDSQSNpKAFVLTLCHHQKIKNFQIlpcEDDGQTFFTLDDGnTKFSDLIQLVD 519
Cdd:cd10345    2 WFHGKISREESEQIVLIGSKTNGKFLIRARDNN-GSYALCLLHEGKVLHYRI---DKDKTGKLSIPEG-KKFDTLWQLVE 76
                         90
                 ....*....|....*..
gi 294979209 520 FYQLNKGVLPCKLKHHC 536
Cdd:cd10345   77 HYSYKADGLLRVLTVPC 93
SH2_SHB_SHD_SHE_SHF_like cd09945
Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, ...
438-535 2.70e-05

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198198  Cd Length: 98  Bit Score: 43.19  E-value: 2.70e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIkqQGLVDGLFLLRDSQSNPKAFVLTL-----CHHQKIKNfqilpcEDDGQtfFTLDDGNTKFS 512
Cdd:cd09945    1 QGWYHGAITRIEAESLL--RPCKEGSYLVRNSESTKQDYSLSLksakgFMHMRIQR------NETGQ--YILGQFSRPFE 70
                         90       100
                 ....*....|....*....|...
gi 294979209 513 DLIQLVDFYQLNKgvLPCKLKHH 535
Cdd:cd09945   71 TIPEMIRHYCLNK--LPVRGAEH 91
SH2_Src_HCK cd10363
Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type ...
437-537 3.17e-05

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in hemopoietic cells. HCK is proposed to couple the Fc receptor to the activation of the respiratory burst. It may also play a role in neutrophil migration and in the degranulation of neutrophils. It has two different translational starts that have different subcellular localization. HCK has been shown to interact with BCR gene, ELMO1 Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. HCK has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198226  Cd Length: 104  Bit Score: 43.03  E-value: 3.17e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTL-----CHHQKIKNFQILpceddgqtffTLDDG---- 507
Cdd:cd10363    2 TEEWFFKGISRKDAERQLLAPGNMLGSFMIRDSETTKGSYSLSVrdydpQHGDTVKHYKIR----------TLDNGgfyi 71
                         90       100       110
                 ....*....|....*....|....*....|..
gi 294979209 508 --NTKFSDLIQLVDFYQLNKGVLPCKLKHHCI 537
Cdd:cd10363   72 spRSTFSTLQELVDHYKKGNDGLCQKLSVPCM 103
SH2_Vav_family cd09940
Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several ...
438-524 4.79e-05

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, Vav2 and Vav3 are more ubiquitously expressed. The members here include insect and amphibian Vavs. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198193  Cd Length: 102  Bit Score: 42.28  E-value: 4.79e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIKqqGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPcEDDGqtFFTLDDgNTKFSDLIQL 517
Cdd:cd09940    5 FLWFVGEMERDTAENRLE--NRPDGTYLVRVRPQGETQYALSIKYNGDVKHMKIEQ-RSDG--LYYLSE-SRHFKSLVEL 78

                 ....*..
gi 294979209 518 VDFYQLN 524
Cdd:cd09940   79 VNYYERN 85
SH2_Vav2 cd10406
Src homology 2 (SH2) domain found in the Vav2 proteins; Proto-oncogene vav is a member of the ...
440-522 4.79e-05

Src homology 2 (SH2) domain found in the Vav2 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav2 is a GEF for RhoA, RhoB and RhoG and may activate Rac1 and Cdc42. Vav2 has been shown to interact with CD19 and Grb2. Alternatively spliced transcript variants encoding different isoforms have been found for Vav2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198269  Cd Length: 103  Bit Score: 42.36  E-value: 4.79e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQglVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpcEDDGQTFFTlddGNTKFSDLIQLVD 519
Cdd:cd10406    7 WFAGNMERQQTDNLLKSH--ASGTYLIRERPAEAERFAISIKFNDEVKHIKVV--EKDNWIHIT---EAKKFESLLELVE 79

                 ...
gi 294979209 520 FYQ 522
Cdd:cd10406   80 YYQ 82
RA_ARAPs cd17113
Ras-associating (RA) domain found in Arf-GAP with Rho-GAP domain, ANK repeat and PH ...
118-197 5.94e-05

Ras-associating (RA) domain found in Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing proteins ARAP1, ARAP2, ARAP3, and similar proteins; ARAPs are phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3))-dependent Arf Rap-activated guanosine triphosphatase (GTPase)-activating proteins (GAPs). They contain multiple functional domains, including ArfGAP and RhoGAP domains, as well as a sterile alpha motif (Sam) domain, five PH domains, and a RA domain. The RA domain has the beta-grasp ubiquitin-like fold with low sequence similarity to ubiquitin (Ub); Ub is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair in eukaryotes.


Pssm-ID: 340633  Cd Length: 95  Bit Score: 41.85  E-value: 5.94e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSH-CVDDNSWTLVEHHPQLGLERCLED----HEIVVQVESTMPSESKFL 192
Cdd:cd17113    8 VYIEEKEGTSVNIKVTPTMTAEEVVEQALNKKNlGGPEGNWALFEVIEDGGLERPLHEsekvLDVVLRWSQWPRKSNYLC 87

                 ....*
gi 294979209 193 FRKNY 197
Cdd:cd17113   88 VKKNP 92
SH2_Src_Frk cd10369
Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src ...
440-532 6.19e-05

Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src non-receptor type tyrosine kinase family of proteins. The Frk subfamily is composed of Frk/Rak and Iyk/Bsk/Gst. It is expressed primarily epithelial cells. Frk is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth. Unlike the other Src members it lacks a glycine at position 2 of SH4 which is important for addition of a myristic acid moiety that is involved in targeting Src PTKs to cellular membranes. FRK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where both induce PC12 cell differentiation and beta-cell proliferation. Under conditions that cause beta-cell degeneration these proteins augment beta-cell apoptosis. The FRK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Frk has been demonstrated to interact with retinoblastoma protein. Frk regulates PTEN protein stability by phosphorylating PTEN, which in turn prevents PTEN degradation. Frk also plays a role in regulation of embryonal pancreatic beta cell formation. Frk has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its activation loop. The tryosine involved is at the same site as the tyrosine involved in the autophosphorylation of Src. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199831  Cd Length: 96  Bit Score: 42.17  E-value: 6.19e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGqtfFTLDDGNTkFSDLIQLVD 519
Cdd:cd10369    5 WFFGAIKRADAEKQLLYSENQTGAFLIRESESQKGEFSLSVLDGGVVKHYRIRRLDEGG---FFLTRRKT-FSTLNEFVN 80
                         90
                 ....*....|...
gi 294979209 520 FYQLNKGVLPCKL 532
Cdd:cd10369   81 YYTTTSDGLCVKL 93
SH2_Src_Fyn_isoform_a_like cd10418
Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src ...
438-532 8.86e-05

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform a type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198281  Cd Length: 101  Bit Score: 41.91  E-value: 8.86e-05
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 438 QHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTL----------CHHQKIKNFqilpceDDGQTFFTLddg 507
Cdd:cd10418    3 EEWYFGKLGRKDAERQLLSFGNPRGTFLIRESETTKGAYSLSIrdwddmkgdhVKHYKIRKL------DNGGYYITT--- 73
                         90       100
                 ....*....|....*....|....*
gi 294979209 508 NTKFSDLIQLVDFYQLNKGVLPCKL 532
Cdd:cd10418   74 RAQFETLQQLVQHYSERAAGLCCRL 98
SH2_DAPP1_BAM32_like cd10355
Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( ...
440-521 1.58e-04

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198218  Cd Length: 92  Bit Score: 40.54  E-value: 1.58e-04
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILpceddgQTFFTLDDGNTKFSDLIQLVD 519
Cdd:cd10355    8 WYHGNLTRHAAEALLLSNG-VDGSYLLRNSNEGTGLFSLSVRAKDSVKHFHVE------YTGYSFKFGFNEFSSLQDFVK 80

                 ..
gi 294979209 520 FY 521
Cdd:cd10355   81 HF 82
SH2_SH2B2 cd10411
Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), ...
440-499 2.88e-04

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198274  Cd Length: 97  Bit Score: 39.99  E-value: 2.88e-04
                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 294979209 440 WFHGRISREESHRIIKQQGLVD-GLFLLRDSQSNPKAFVLTLCHHQKIKNFQiLPCEDDGQ 499
Cdd:cd10411   10 WFHGTLSRVKAAQLVLAGGPRShGLFVIRQSETRPGEYVLTFNFQGKAKHLR-LSLNGHGQ 69
SH2_BLNK_SLP-76 cd09929
Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing ...
437-528 3.28e-04

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198183  Cd Length: 121  Bit Score: 40.37  E-value: 3.28e-04
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISR---EESHRIIKQqglvDGLFLLRDSqSNPKA---FVLTLCHHQKIKNFQIlPCEDDGQTFF--TLDDGN 508
Cdd:cd09929   10 PKEWYAGNIDRkeaEEALRRSNK----DGTFLVRDS-SGKDSsqpYTLMVLYNDKVYNIQI-RFLENTRQYAlgTGLRGE 83
                         90       100
                 ....*....|....*....|
gi 294979209 509 TKFSDLIQLVDFYQLNKGVL 528
Cdd:cd09929   84 ETFSSVAEIIEHHQKTPLLL 103
SH2_Tensin_like cd09927
Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. ...
437-480 3.75e-04

Src homology 2 domain found in Tensin-like proteins; SH2 domain found in Tensin-like proteins. The Tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: Tensin1, Tensin2 (TENC1, C1-TEN), Tensin3 and Tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of Tensin2 and Tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein. PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway. Because of their PTEN-like domains, the Tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only Tensin2 and Tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198181 [Multi-domain]  Cd Length: 116  Bit Score: 40.10  E-value: 3.75e-04
                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 294979209 437 TQHWFHGRISREESHRIIKQQglVDGLFLLRDSQSNPKAFVLTL 480
Cdd:cd09927    2 SKYWYKPNISRDQAIALLKDK--PPGTFLVRDSTTYKGAYGLAV 43
SH2_Jak_family cd09921
Src homology 2 (SH2) domain in the Janus kinase (Jak) family; The Janus kinases (Jak) are a ...
441-522 4.65e-04

Src homology 2 (SH2) domain in the Janus kinase (Jak) family; The Janus kinases (Jak) are a family of 4 non-receptor tyrosine kinases (Jak1, Jak2, Jak3, Tyk2) which respond to cytokine or growth factor receptor activation. To transduce cytokine signaling, a series of conformational changes occur in the receptor-Jak complex upon extracellular ligand binding. This results in trans-activation of the receptor-associated Jaks followed by phosphorylation of receptor tail tyrosine sites. The Signal Transducers and Activators of Transcription (STAT) are then recruited to the receptor tail, become phosphorylated and translocate to the nucleus to regulate transcription. Jaks have four domains: the pseudokinase domain, the catalytic tyrosine kinase domain, the FERM (band four-point-one, ezrin, radixin, and moesin) domain, and the SH2 (Src Homology-2) domain. The Jak kinases are regulated by several enzymatic and non-enzymatic mechanisms. First, the Jak kinase domain is regulated by phosphorylation of the activation loop which is associated with the catalytically competent kinase conformation and is distinct from the inactive kinase conformation. Second, the pseudokinase domain directly modulates Jak catalytic activity with the FERM domain maintaining an active state. Third, the suppressor of cytokine signaling (SOCS) family and tyrosine phosphatases directly regulate Jak activity. Dysregulation of Jak activity can manifest as either a reduction or an increase in kinase activity resulting in immunodeficiency, inflammatory diseases, hematological defects, autoimmune and myeloproliferative disorders, and susceptibility to infection. Altered Jak regulation occurs by many mechanisms, including: gene translocations, somatic or inherited point mutations, receptor mutations, and alterations in the activity of Jak regulators such as SOCS or phosphatases. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198177  Cd Length: 97  Bit Score: 39.58  E-value: 4.65e-04
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 441 FHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLC----HHQKIKNFQIlpcEDDGQTFFTLDDGNTKFSDLIQ 516
Cdd:cd09921   15 CHGPIGGEFSYRKLKERGNKPGSYILRESETEYDTYYIDVCvkdgSRFQTKTFKI---EKKEGGVFFLDGDSREYPSLRD 91

                 ....*.
gi 294979209 517 LVDFYQ 522
Cdd:cd09921   92 LLNSLQ 97
SH2_Src_Fgr cd10367
Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene ...
436-527 5.26e-04

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, Fgr; Fgr is a member of the Src non-receptor type tyrosine kinase family of proteins. The protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. Fgr is expressed in B-cells and myeloid cells, localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified Fgr has been shown to interact with Wiskott-Aldrich syndrome protein. Fgr has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198230  Cd Length: 101  Bit Score: 39.50  E-value: 5.26e-04
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 436 RTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTL----------CHHQKIKNFqilpceDDGQTFFTLd 505
Cdd:cd10367    1 QAEEWYFGKIGRKDAERQLLSPGNPRGAFLIRESETTKGAYSLSIrdwdqnrgdhVKHYKIRKL------DTGGYYITT- 73
                         90       100
                 ....*....|....*....|...
gi 294979209 506 dgNTKFSDLIQLVDFY-QLNKGV 527
Cdd:cd10367   74 --RAQFDTVQELVQHYmEVNDGL 94
SH2_SH2B3 cd10412
Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), ...
440-491 5.73e-04

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198275  Cd Length: 97  Bit Score: 39.11  E-value: 5.73e-04
                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 294979209 440 WFHGRISREESHRIIKQQGL-VDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQI 491
Cdd:cd10412   10 WFHGPISRVKAAQLVQLQGPdAHGVFLVRQSETRRGEYVLTFNFQGRAKHLRL 62
SH2_PTK6_Brk cd10358
Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast ...
437-530 1.01e-03

Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast tumor kinase (Brk); Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumors. PTK6 (9). PTK6 contains a SH3 domain, a SH2 domain, and catalytic domains. For the case of the non-receptor protein-tyrosine kinases, the SH2 domain is typically involved in negative regulation of kinase activity by binding to a phosphorylated tyrosine residue near to the C terminus. The C-terminal sequence of PTK6 (PTSpYENPT where pY is phosphotyrosine) is thought to be a self-ligand for the SH2 domain. The structure of the SH2 domain resembles other SH2 domains except for a centrally located four-stranded antiparallel beta-sheet (strands betaA, betaB, betaC, and betaD). There are also differences in the loop length which might be responsible for PTK6 ligand specificity. There are two possible means of regulation of PTK6: autoinhibitory with the phosphorylation of Tyr playing a role in its negative regulation and autophosphorylation at this site, though it has been shown that PTK6 might phosphorylate signal transduction-associated proteins Sam68 and signal transducing adaptor family member 2 (STAP/BKS) in vivo. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198221  Cd Length: 100  Bit Score: 38.57  E-value: 1.01e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPcEDDGQTFFtldDGNTKFSDLIQ 516
Cdd:cd10358    1 SEPWFFGCISRSEAVRRLQAEGNATGAFLIRVSEKPSADYVLSVRDTQAVRHYKIWR-RAGGRLHL---NEAVSFLSLPE 76
                         90       100
                 ....*....|....*....|
gi 294979209 517 LVDFYQ---LNKGV---LPC 530
Cdd:cd10358   77 LVNYHRaqsLSHGLrlaAPC 96
SH2_RIN2 cd10394
Src homology 2 (SH2) domain found in Ras and Rab interactor 2 (RIN2)-like proteins; RIN2, a ...
430-529 1.10e-03

Src homology 2 (SH2) domain found in Ras and Rab interactor 2 (RIN2)-like proteins; RIN2, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. Ras induces activation of Rab5 through RIN2, which is a direct downstream target of Ras and a direct upstream regulator of Rab5. In other words it is the binding of the GTP-bound form of Ras to the RA domain of RIN2 that enhances the GEF activity toward Rab5. It is thought that the RA domain negatively regulates the Rab5 GEF activity. In steady state, RIN2 is likely to form a closed conformation by an intramolecular interaction between the RA domain and the Vps9p-like (Rab5 GEF) domain, negatively regulating the Rab5 GEF activity. In the active state, the binding of Ras to the RA domain may reduce the intramolecular interaction and stabilize an open conformation of RIN2. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198257  Cd Length: 100  Bit Score: 38.64  E-value: 1.10e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 430 LNAVIHRTQHWFHGRISREESHRIIKQQGlvDGLFLLRDSQSNPKafvltlchhqKIKNFQiLPCEDD----------GQ 499
Cdd:cd10394    2 LDRLLHTHPIWLQLSLSEEEAAEVLQAQP--PGIFLVRKSSKMQK----------KVLSLR-LPCEFGaplkefaikeST 68
                         90       100       110
                 ....*....|....*....|....*....|
gi 294979209 500 TFFTLDDGNTKFSDLIQLVDFYQLNKGVLP 529
Cdd:cd10394   69 YTFSLEGSGISFADLFRLIAFYCISRDVLP 98
PH_GRP1-like cd01252
General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 ...
239-279 1.36e-03

General Receptor for Phosphoinositides-1-like Pleckstrin homology (PH) domain; GRP1/cytohesin3 and the related proteins ARNO (ARF nucleotide-binding site opener)/cytohesin-2 and cytohesin-1 are ARF exchange factors that contain a pleckstrin homology (PH) domain thought to target these proteins to cell membranes through binding polyphosphoinositides. The PH domains of all three proteins exhibit relatively high affinity for PtdIns(3,4,5)P3. Within the Grp1 family, diglycine (2G) and triglycine (3G) splice variants, differing only in the number of glycine residues in the PH domain, strongly influence the affinity and specificity for phosphoinositides. The 2G variants selectively bind PtdIns(3,4,5)P3 with high affinity,the 3G variants bind PtdIns(3,4,5)P3 with about 30-fold lower affinity and require the polybasic region for plasma membrane targeting. These ARF-GEFs share a common, tripartite structure consisting of an N-terminal coiled-coil domain, a central domain with homology to the yeast protein Sec7, a PH domain, and a C-terminal polybasic region. The Sec7 domain is autoinhibited by conserved elements proximal to the PH domain. GRP1 binds to the DNA binding domain of certain nuclear receptors (TRalpha, TRbeta, AR, ER, but not RXR), and can repress thyroid hormone receptor (TR)-mediated transactivation by decreasing TR-complex formation on thyroid hormone response elements. ARNO promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion. Cytohesin acts as a PI 3-kinase effector mediating biological responses including cell spreading and adhesion, chemotaxis, protein trafficking, and cytoskeletal rearrangements, only some of which appear to depend on their ability to activate ARFs. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.


Pssm-ID: 269954  Cd Length: 119  Bit Score: 38.83  E-value: 1.36e-03
                         10        20        30        40
                 ....*....|....*....|....*....|....*....|..
gi 294979209 239 PEIQGFLqVKEVGR-KSWKKLYVCLRRSGLYYSTKGTSKEPR 279
Cdd:cd01252    3 PDREGWL-LKLGGRvKSWKRRWFILTDNCLYYFEYTTDKEPR 43
SH2_Jak3 cd10380
Src homology 2 (SH2) domain in the Janus kinase 3 (Jak3) proteins; Jak3 is a member of the ...
442-522 1.60e-03

Src homology 2 (SH2) domain in the Janus kinase 3 (Jak3) proteins; Jak3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198243  Cd Length: 96  Bit Score: 37.84  E-value: 1.60e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 442 HGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHH----QKIKNFQILPCEDDgqtfFTLDDGNTKFSDLIQL 517
Cdd:cd10380   16 HGPITSEFAVNKLKKAGSEPGSFVLRRSPQDFDKFLLTVCVQttlgLDYKDCLIRKNEGH----FSLAGVSRSFSSLKEL 91

                 ....*
gi 294979209 518 VDFYQ 522
Cdd:cd10380   92 LVTYQ 96
SH2_SH2D4A cd10350
Src homology 2 domain found in the SH2 domain containing protein 4A (SH2D4A); SH2D4A contains ...
440-522 2.46e-03

Src homology 2 domain found in the SH2 domain containing protein 4A (SH2D4A); SH2D4A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198213  Cd Length: 103  Bit Score: 37.60  E-value: 2.46e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIkqQGLVDGLFLLRDSQsNPKAFVLTLCHHQKIKNFqILPCEDDGQTFFTLDdgNTKFSDLIQLVD 519
Cdd:cd10350    9 WFHGILTLKKANELL--LSTMPGSFLIRVSE-KIKGYALSYLSEEGCKHF-LIDASADSYSFLGVD--QLQHATLADLVE 82

                 ...
gi 294979209 520 FYQ 522
Cdd:cd10350   83 YHK 85
B41 smart00295
Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in ...
118-206 3.34e-03

Band 4.1 homologues; Also known as ezrin/radixin/moesin (ERM) protein domains. Present in myosins, ezrin, radixin, moesin, protein tyrosine phosphatases. Plasma membrane-binding domain. These proteins play structural and regulatory roles in the assembly and stabilization of specialized plasmamembrane domains. Some PDZ domain containing proteins bind one or more of this family. Now includes JAKs.


Pssm-ID: 214604 [Multi-domain]  Cd Length: 201  Bit Score: 38.82  E-value: 3.34e-03
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209   118 VKVFSEDGTSKVVEILTDMTARDLCQLLVYKSHCVDDNSWTLVEHHPQLGLERCLE-DHEIVVQVEStmPSESKFLFRKN 196
Cdd:smart00295   2 LKVYLLDGTTLEFEVDSSTTAEELLETVCRKLGIRESEYFGLQFEDPDEDLRHWLDpAKTLLDQDVK--SEPLTLYFRVK 79
                           90
                   ....*....|
gi 294979209   197 YakyeFFKNP 206
Cdd:smart00295  80 F----YPPDP 85
SH2_Tec_Txk cd10398
Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine ...
437-534 3.56e-03

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198261  Cd Length: 106  Bit Score: 37.23  E-value: 3.56e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGlVDGLFLLRDSQS----NPKAFVLTLCHHQ-KIKNFQILPcEDDGQTFFTlddGNTKF 511
Cdd:cd10398    5 IYEWYHKNITRNQAERLLRQES-KEGAFIVRDSRHlgsyTISVFTRARRSTEaSIKHYQIKK-NDSGQWYVA---ERHLF 79
                         90       100
                 ....*....|....*....|...
gi 294979209 512 SDLIQLVDFYQLNKGVLPCKLKH 534
Cdd:cd10398   80 QSIPELIQYHQHNAAGLMSRLRY 102
SH2_SH2D2A cd10416
Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains ...
440-516 4.20e-03

Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198279  Cd Length: 102  Bit Score: 36.94  E-value: 4.20e-03
                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 294979209 440 WFHGRISREESHRIIKQQGLvdGLFLLRDSQSnPKAFVLTLCHHQKIKNFQILPCEDDGQTFFTLDDGNTKFSDLIQ 516
Cdd:cd10416    9 WFHGFITRREAERLLEPKPQ--GCYLVRFSES-AVTFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARLQDLLL 82
SH2_SH2B1 cd10410
Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B1 (SH2-B, ...
440-499 5.85e-03

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B1 (SH2-B, PSM), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198273  Cd Length: 97  Bit Score: 36.53  E-value: 5.85e-03
                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 294979209 440 WFHGRISREESHRIIKQQGLVD-GLFLLRDSQSNPKAFVLTLCHHQKIKNFQiLPCEDDGQ 499
Cdd:cd10410   10 WFHGMLSRLKAAQLVLEGGTGShGVFLVRQSETRRGEYVLTFNFQGKAKHLR-LSLNEEGQ 69
SH2_SOCS_family cd09923
Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 ...
440-521 7.33e-03

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198178  Cd Length: 81  Bit Score: 35.64  E-value: 7.33e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlvDGLFLLRDS-QSNpkaFVLTL--------CH---HQKIKNFQilpceddgqtFFTLDDG 507
Cdd:cd09923    2 WYWGGITRYEAEELLAGKP--EGTFLVRDSsDSR---YLFSVsfrtygrtLHariEYSNGRFS----------FDSSDPS 66
                         90
                 ....*....|....
gi 294979209 508 NTKFSDLIQLVDFY 521
Cdd:cd09923   67 VPRFPCVVELIEHY 80
SH2_SH2D4B cd10351
Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains ...
440-522 7.89e-03

Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198214  Cd Length: 103  Bit Score: 36.02  E-value: 7.89e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQglVDGLFLLRDSQsNPKAFVLTLCHHQKIKNFqILPCEDDGQTFFTLDDgnTKFSDLIQLVD 519
Cdd:cd10351    9 WFHGIISREEAEALLMNA--TEGSFLVRVSE-KIWGYTLSYRLQSGFKHF-LVDASGDFYSFLGVDP--NRHATLTDLID 82

                 ...
gi 294979209 520 FYQ 522
Cdd:cd10351   83 FHK 85
SH2_Tec_Bmx cd10399
Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine ...
440-534 9.25e-03

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine kinase Bmx is expressed in the endothelium of large arteries, fetal endocardium, adult endocardium of the left ventricle, bone marrow, lung, testis, granulocytes, myeloid cell lines, and prostate cell lines. Bmx is involved in the regulation of Rho and serum response factor (SRF). Bmx has been shown to interact with PAK1, PTK2, PTPN21, and RUFY1. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains. It is not present in Txk and the type 1 splice form of the Drosophila homolog. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198262  Cd Length: 106  Bit Score: 36.09  E-value: 9.25e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 440 WFHGRISREESHRIIKQQGlVDGLFLLRDSQSNPK--AFVLTLCHHQK---IKNFQIlpcEDDGQTFFTLDDgNTKFSDL 514
Cdd:cd10399    8 WFAGNISRSQSEQLLRQKG-KEGAFMVRNSSQVGMytVSLFSKAVNDKkgtVKHYHV---HTNAENKLYLAE-NYCFDSI 82
                         90       100
                 ....*....|....*....|
gi 294979209 515 IQLVDFYQLNKGVLPCKLKH 534
Cdd:cd10399   83 PKLIHYHQHNSAGMITRLRH 102
SH2_Src_Src42 cd10370
Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the ...
437-522 9.28e-03

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the Src non-receptor type tyrosine kinase family of proteins. The integration of receptor tyrosine kinase-induced RAS and Src42 signals by Connector eNhancer of KSR (CNK) as a two-component input is essential for RAF activation in Drosophila. Src42 is present in a wide variety of organisms including: California sea hare, pea aphid, yellow fever mosquito, honey bee, Panamanian leafcutter ant, and sea urchin. Src42 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198233  Cd Length: 96  Bit Score: 35.94  E-value: 9.28e-03
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 294979209 437 TQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGqtFFTLDdgNTKFSDLIQ 516
Cdd:cd10370    2 AEPWYFGKIKRIEAEKKLLLPENEHGAFLIRDSESRHNDYSLSVRDGDTVKHYRIRQLDEGG--FFIAR--RTTFRTLQE 77

                 ....*.
gi 294979209 517 LVDFYQ 522
Cdd:cd10370   78 LVEHYS 83
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
  • Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
  • Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
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