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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 388 IHRTQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 467
Cdd:cd10413     1 IHRTQPWFHGRISREESQRLIGQQGLVDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 80

                          90       100
                  ....*....|....*....|....*...
gi 1622879398 468 LLQLVEFHQLNRGILPCLLRHCCTRVAL 495
Cdd:cd10413    81 LLQLVEFHQLNRGILPCLLRHCCTRVAL 108

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 225 NAGSFPEIQGFLQLRGSGRKLWKRFFCFLRRSGLYYSTKGTS-------------------------------------K 267
Cdd:cd01259     1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSkesrdlqclaqfddynvytglngkkkykaptdfgfclK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1622879398 268 PNKLR-NGHKGLRIFCSEDEQSRTCWLAAFRLFKYGVQLYRNYQ 310
Cdd:cd01259    81 PNKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 388 IHRTQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 467
Cdd:cd10413     1 IHRTQPWFHGRISREESQRLIGQQGLVDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 80

                          90       100
                  ....*....|....*....|....*...
gi 1622879398 468 LLQLVEFHQLNRGILPCLLRHCCTRVAL 495
Cdd:cd10413    81 LLQLVEFHQLNRGILPCLLRHCCTRVAL 108

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 225 NAGSFPEIQGFLQLRGSGRKLWKRFFCFLRRSGLYYSTKGTS-------------------------------------K 267
Cdd:cd01259     1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSkesrdlqclaqfddynvytglngkkkykaptdfgfclK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1622879398 268 PNKLR-NGHKGLRIFCSEDEQSRTCWLAAFRLFKYGVQLYRNYQ 310
Cdd:cd01259    81 PNKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1622879398 328 RSVSDNTLVAMDFSGHAGRVIENPREALSVALEEAHAWRKKTNHRL 373
Cdd:pfam08947   1 RSVSESSLVAMDFSGAGGRVIENPEEALSEAEEEGAAWRKKTLRRC 46

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.)

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398  100 RPHVVKVYSED---GACRSVEVAAGATARHVCEMLVQRAHALSD-ETWGLVECHPHlALERGLEDHESVVEVQAAWPVGG 175
Cdd:smart00314   1 DTFVLRVYVDDlpgGTYKTLRVSSRTTARDVIQQLLEKFHLTDDpEEYVLVEVLPD-GKERVLPDDENPLQLQKLWPRRG 79

                           90
                   ....*....|
gi 1622879398  176 DS-RFVFRKN 184
Cdd:smart00314  80 PNlRFVLRKR 89

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398  230 PEIQGFLQLRGS-GRKLWKRFFCFLRRSGLYYSTKGTSKPN-----------------------------KLRNGHKGLR 279
Cdd:smart00233   1 VIKEGWLYKKSGgGKKSWKKRYFVLFNSTLLYYKSKKDKKSykpkgsidlsgctvreapdpdsskkphcfEIKTSDRKTL 80

                           90
                   ....*....|....*...
gi 1622879398  280 IFCSEDEQSRTCWLAAFR 297
Cdd:smart00233  81 LLQAESEEEREKWVEALR 98

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 388 IHRTQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 467
Cdd:cd10413     1 IHRTQPWFHGRISREESQRLIGQQGLVDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 80

                          90       100
                  ....*....|....*....|....*...
gi 1622879398 468 LLQLVEFHQLNRGILPCLLRHCCTRVAL 495
Cdd:cd10413    81 LLQLVEFHQLNRGILPCLLRHCCTRVAL 108

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 100 RPHVVKVYSEDGACRSVEVAAGATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAWPVGGDSRF 179
Cdd:cd16140     1 GPHVVKVYSEDGTCRSLEVTAGATARHVCEMLVQRAHCLDDESWSLVELHPHLALERCLEDHESVVEVQATWPAGGDSRF 80

                  ....*...
gi 1622879398 180 VFRKNFAK 187
Cdd:cd16140    81 VFRKNFAK 88

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 388 IHRTQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDGQTRFTD 467
Cdd:cd10415     1 IHRTQHWFHGRISREESHRIIKQQGLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFSLDDGNTKFSD 80

                          90       100
                  ....*....|....*....|....*...
gi 1622879398 468 LLQLVEFHQLNRGILPCLLRHCCTRVAL 495
Cdd:cd10415    81 LIQLVDFYQLNKGVLPCKLKHHCIRVAL 108

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 225 NAGSFPEIQGFLQLRGSGRKLWKRFFCFLRRSGLYYSTKGTS-------------------------------------K 267
Cdd:cd01259     1 NSVSCPEIEGFLYLKEDGKKSWKKRYFVLRASGLYYSPKGKSkesrdlqclaqfddynvytglngkkkykaptdfgfclK 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1622879398 268 PNKLR-NGHKGLRIFCSEDEQSRTCWLAAFRLFKYGVQLYRNYQ 310
Cdd:cd01259    81 PNKQQeKGSKDIKYLCAEDEQSRTCWLTAIRLAKYGKQLYENYR 124

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 103 VVKVYSEDGACRSVEVAAGATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAWPVGGDSRFVFR 182
Cdd:cd17112     1 VVKVYNEDGSSKTVAVDENMTARDVCQILVEKNHVDPDKSWSLVEELPELGLERTLEDHELVVDVYSKWPSDSNNKFLFR 80

                  .
gi 1622879398 183 K 183
Cdd:cd17112    81 K 81

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398  392 QLWFHGRISREESQRLIGQQGlvDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSeEEGRLYFsmdDGQTRFTDLLQL 471
Cdd:smart00252   1 QPWYHGFISREEAEKLLKNEG--DGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRN-EDGKFYL---EGGRKFPSLVEL 74

                   ....*...
gi 1622879398  472 VEFHQLNR 479
Cdd:smart00252  75 VEHYQKNS 82

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIgQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILpSEEEGRLYFSmddGQTRFTDLLQLVE 473
Cdd:pfam00017   1 WYHGKISRQEAERLL-LNGKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQ-STDNGGYYIS---GGVKFSSLAELVE 75

                  ..
gi 1622879398 474 FH 475
Cdd:pfam00017  76 HY 77

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIgqQGLVDGLFLVRESQRNPQGFVLSLCH-LQKVKHYLILPSEEEgrlYFSMDDGQTRFTDLLQLV 472
Cdd:cd00173     2 WFHGSISREEAERLL--RGKPDGTFLVRESSSEPGDYVLSVRSgDGKVKHYLIERNEGG---YYLLGGSGRTFPSLPELV 76

                  ...
gi 1622879398 473 EFH 475
Cdd:cd00173    77 EHY 79

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLIlpsEEEGRLYFSMDDGQTrFTDLLQLVE 473
Cdd:cd09938     3 FFYGSITREEAEEYLKLAGMSDGLFLLRQSLRSLGGYVLSVCHGRKFHHYTI---ERQLNGTYAIAGGKA-HCGPAELCE 78

                          90
                  ....*....|....*....
gi 1622879398 474 FHQLNRGILPCLLRHCCTR 492
Cdd:cd09938    79 YHSTDLDGLVCLLRKPCNR 97

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 392 QLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLIlpsEEEGRLYFSMDDGQTRFTDLLQL 471
Cdd:cd10347     1 LRWYHGKISREVAEALLLREGGRDGLFLVRESTSAPGDYVLSLLAQGEVLHYQI---RRHGEDAFFSDDGPLIFHGLDTL 77

                  ....
gi 1622879398 472 VEFH 475
Cdd:cd10347    78 IEHY 81

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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1622879398 103 VVKVYSEDGACRSVEVAAGATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAW 171
Cdd:cd01787     3 VVKVHMEDGSSKTLLVDERMTVRQVLKQLIEKNHCDPSVDWCLVEQYPDLYMERVFEDHEKLVENLLNW 71

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 389 HRTQLWFHGRISREESQRLIGQQGLVDGLFLVREsqRNPQG-FVLSLCHLQKVKHYLILpSEEEGRlyFSMDDGqTRFTD 467
Cdd:cd10402     7 HERMPWYHGSIARDEAERRLYSGAQPDGKFLLRE--RKESGtYALSLVYGKTVYHYRID-QDKSGK--YSIPEG-TKFDT 80

                          90       100
                  ....*....|....*....|...
gi 1622879398 468 LLQLVEFHQLNR-GILPCLLRHC 489
Cdd:cd10402    81 LWQLVEYLKLKPdGLIFVLRESC 103

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIgQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILpSEEEGRLYFsmddGQTRFTDLLQLVE 473
Cdd:cd09941     5 WFHGKISRAEAEEIL-MNQRPDGAFLIRESESSPGDFSLSVKFGNDVQHFKVL-RDGAGKYFL----WVVKFNSLNELVD 78

                  ...
gi 1622879398 474 FHQ 476
Cdd:cd09941    79 YHR 81

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622879398 394 WFHGRISREESQRLIGQQGlVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEE-----GRLYFSMDD 460
Cdd:cd10354     2 WFHGKISREEAYNMLVKVG-GPGSFLVRESDNTPGDYSLSFRVNEGIKHFKIIPTGNNqfmmgGRYFSSLDD 72

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622879398 104 VKVYSEDGACRSVEVAAGATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAWPVGGDSRFVF 181
Cdd:cd16138     5 VKAFTEDGSAKSLLVDERMTVGHVTRLLADKNHVAMMPDWAIVEHIPDLYMERVYEDHEKLVENLMMWTRDSPNRLLF 82

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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1622879398 390 RTQLWFHGRISREESQRLIGQqglvDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILpsEEEGR 453
Cdd:cd09925     5 RGEPWYHGKMSRRDAESLLQT----DGDFLVRESTTTPGQYVLTGMQNGQPKHLLLV--DPEGV 62

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 389 HRTQLWFHGRISREESQRLigqqgLV-DGLFLVRESQRNPQG---FVLSLCHLQKVKHYLIlpSEEEGRLYFSMDdgqTR 464
Cdd:cd10361     3 LENEPYYHGLLPREDAEEL-----LKnDGDFLVRKTEPKGGGkrkLVLSVRWDGKIRHFVI--NRDDGGKYYIEG---KS 72

                          90
                  ....*....|..
gi 1622879398 465 FTDLLQLVEFHQ 476
Cdd:cd10361    73 FKSISELINYYQ 84

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 103 VVKVYSED----GACRSVEVAAGATARHVCEMLVQRAH-ALSDETWGLVECHPHLALERGLEDHESVVEVQAAW-PVGGD 176
Cdd:cd17043     1 VLKVYDDDlapgSAYKSILVSSTTTAREVVQLLLEKYGlEEDPEDYSLYEVSEKQETERVLHDDECPLLIQLEWgPQGTE 80

                  ....*..
gi 1622879398 177 SRFVFRK 183
Cdd:cd17043    81 FRFVLKR 87

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 389 HRTQLWFHGRIS--REESQRLIGQ-QGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRL-YFSMDDGQtr 464
Cdd:cd10341     1 HFTEPWFHGKLGdgRDEAEKLLLEyCEGGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIRSRQENGEKkYYLTDNLV-- 78

                          90
                  ....*....|....*
gi 1622879398 465 FTDLLQLVEFHQLNR 479
Cdd:cd10341    79 FDSLYELIDYYRQNP 93

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 392 QLWFHGRISREESQRLIGQQGlVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLIlpSEEEGRLYFsmddGQTRFTDLLQL 471
Cdd:cd09943     1 QPWYYGRITRHQAETLLNEHG-HEGDFLIRDSESNPGDYSVSLKAPGRNKHFKV--QVVDNVYCI----GQRKFHTMDEL 73

                  ....*
gi 1622879398 472 VEFHQ 476
Cdd:cd09943    74 VEHYK 78

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 103 VVKVYSEDGACRSVEVAAGATARHVCEMLVQRAHALSDETWGLVECHPHLALERGLEDHESVVEVQAAWPVGGDSRFVFR 182
Cdd:cd16136     6 VIRVHMSDDSSKTMMVDERQTVRQVLDNLMDKSHCGYSLDWSLVETISELQMERIFEDHENLVENLLNWTRDSQNKLMFV 85

                  ....*
gi 1622879398 183 KNFAK 187
Cdd:cd16136    86 ERIEK 90

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIGqqGLVDGLFLVRESQRnPQGFVLSLCHLQKVKHYLIlpsEEEGRLYFSMDDGQTRFTDLLQLVE 473
Cdd:cd10350     9 WFHGILTLKKANELLL--STMPGSFLIRVSEK-IKGYALSYLSEEGCKHFLI---DASADSYSFLGVDQLQHATLADLVE 82

                  ...
gi 1622879398 474 FHQ 476
Cdd:cd10350    83 YHK 85

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 395 FHGRISREESQRLIGqqGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYlilpseeegRLYFSMDD-----GQTRFTDLL 469
Cdd:cd10352     9 YHGLISREEAEQLLS--GASDGSYLIRESSRDDGYYTLSLRFNGKVKNY---------KLYYDGKNhyhyvGEKRFDTIH 77

                  ...
gi 1622879398 470 QLV 472
Cdd:cd10352    78 DLV 80

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 391 TQLWFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILPSeEEGRLYFsmdDGQTRFTDLLQ 470
Cdd:cd10358     1 SEPWFFGCISRSEAVRRLQAEGNATGAFLIRVSEKPSADYVLSVRDTQAVRHYKIWRR-AGGRLHL---NEAVSFLSLPE 76

                          90       100
                  ....*....|....*....|
gi 1622879398 471 LVEFHQ---LNRGI---LPC 484
Cdd:cd10358    77 LVNYHRaqsLSHGLrlaAPC 96

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 394 WFHGRISREESQRLIGQQGLVDGLFLVRESQRNPQGFVLSLCHLQ-----KVKHYLIlPSEEEGRLYFSmddGQTRFTDL 468
Cdd:cd10365     5 WYFGKITRRESERLLLNAENPRGTFLVRESETTKGAYCLSVSDFDnakglNVKHYKI-RKLDSGGFYIT---SRTQFNSL 80

                  ....*...
gi 1622879398 469 LQLVEFHQ 476
Cdd:cd10365    81 QQLVAYYS 88

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622879398 392 QLWFHGRISREESQRLIgqQGLVDGLFLVRESQRNPQGFVLSLCHLQKVKHYLILpSEEEGRLYFSMDdgqTRFTDLLQL 471
Cdd:cd09940     5 FLWFVGEMERDTAENRL--ENRPDGTYLVRVRPQGETQYALSIKYNGDVKHMKIE-QRSDGLYYLSES---RHFKSLVEL 78