Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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 24654698 651 SETIARHQASFQNFKGPPLHLHSARFFLQVDATRQKQN--LWNSSYTLFLFDNQLVYCKRDIIKRSHFIYKGRIFLDRCR 728
Cdd:cd01224   1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIsaGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDNME 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 24654698 729 VVNVRDGKMF--GHTIKNSLRIYSESRDKWYDFSFRSANRKHRFLSTLALERQFGGKA 784
Cdd:cd01224  81 IEDLPDGKDDesGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 24654698    287 PTTYAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEETnlvedilgpelGWFPKEFVR 353
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKE-----------GLFPSNYVE 56

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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 24654698 651 SETIARHQASFQNFKGPPLHLHSARFFLQVDATRQKQN--LWNSSYTLFLFDNQLVYCKRDIIKRSHFIYKGRIFLDRCR 728
Cdd:cd01224   1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIsaGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDNME 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 24654698 729 VVNVRDGKMF--GHTIKNSLRIYSESRDKWYDFSFRSANRKHRFLSTLALERQFGGKA 784
Cdd:cd01224  81 IEDLPDGKDDesGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698   442 AVRELLDTEVNYVKLLAAICDGYLPAMSKRIDIfSPNSIRLIFSNITAIYKFQRK-FLEALRR-GIEQNQVAKVFLKMHK 519
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSE-SEEEIKTIFSNIEEIYELHRQlLLEELLKeWISIQRIGDIFLKFAP 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698   520 GFLCYSTYCNAYPRALIELETYDRV-KDARTILENCRESQNLAELPLSAHLLAPVQRICRYPLHLNEIIKSalekgakeg 598
Cdd:pfam00621  80 GFKVYSTYCSNYPKALKLLKKLLKKnPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKH--------- 150

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 24654698   599 ndtdgaksagkttdyeqldvTELDIPDSQDtVNLALEAMRGITEAVN 645
Cdd:pfam00621 151 --------------------TPPDHPDYED-LKKALEAIKEVAKQIN 176

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 24654698    287 PTTYAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEETnlvedilgpelGWFPKEFVR 353
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKE-----------GLFPSNYVE 56

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  437 IIRRSAVRELLDTEVNYVKLLAAICDGYLP------AMSKRIDIfspNSIRLIFSNITAIYKFQRKFLEALRR----GIE 506
Cdd:COG5422  483 IKRQEAIYEVIYTERDFVKDLEYLRDTWIKpleesnIIPENARR---NFIKHVFANINEIYAVNSKLLKALTNrqclSPI 559

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  507 QNQVAKVFLKMHKGFLCYSTYCNAYPRALIELETYDRV--KDAR--TILENCRESQNLAelpLSAHLLAPVQRICRYPLH 582
Cdd:COG5422  560 VNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKSVnpNFARfdHEVERLDESRKLE---LDGYLTKPTTRLARYPLL 636

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  583 LNEIIKSalekgAKEGNDtdgaksagkttDYEqldvtelDIPDSQDTVNlalEAMRGITEAVNEGK-RHSETIARHQASF 661
Cdd:COG5422  637 LEEVLKF-----TDPDNP-----------DTE-------DIPKVIDMLR---EFLSRLNFESGKAEnRGDLFHLNQQLLF 690

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  662 QNfKGPPLHLHSARFFLQVDATRQKQNLWNSS------YTLFLFDNQLVYCKRDIIKRSH 715
Cdd:COG5422  691 KP-EYVNLGLNDEYRKIIFKGVLKRKAKSKTDgslrgdIQFFLLDNMLLFCKAKAVNKWR 749

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24654698   696 LFLFDNQLVYCKRDIIKRSHfIYKGRIFLDRCRVVNVRDGKMFGHTIKNSLRIYSESRDKWYDFSFRSANRKHRFLSTL 774
Cdd:pfam00169  23 FVLFDGSLLYYKDDKSGKSK-EPKGSISLSGCEVVEVVASDSPKRKFCFELRTGERTGKRTYLLQAESEEERKDWIKAI 100

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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 24654698 651 SETIARHQASFQNFKGPPLHLHSARFFLQVDATRQKQN--LWNSSYTLFLFDNQLVYCKRDIIKRSHFIYKGRIFLDRCR 728
Cdd:cd01224   1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIsaGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDNME 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 24654698 729 VVNVRDGKMF--GHTIKNSLRIYSESRDKWYDFSFRSANRKHRFLSTLALERQFGGKA 784
Cdd:cd01224  81 IEDLPDGKDDesGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698   442 AVRELLDTEVNYVKLLAAICDGYLPAMSKRIDIfSPNSIRLIFSNITAIYKFQRK-FLEALRR-GIEQNQVAKVFLKMHK 519
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSE-SEEEIKTIFSNIEEIYELHRQlLLEELLKeWISIQRIGDIFLKFAP 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698   520 GFLCYSTYCNAYPRALIELETYDRV-KDARTILENCRESQNLAELPLSAHLLAPVQRICRYPLHLNEIIKSalekgakeg 598
Cdd:pfam00621  80 GFKVYSTYCSNYPKALKLLKKLLKKnPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKH--------- 150

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 24654698   599 ndtdgaksagkttdyeqldvTELDIPDSQDtVNLALEAMRGITEAVN 645
Cdd:pfam00621 151 --------------------TPPDHPDYED-LKKALEAIKEVAKQIN 176

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 24654698    287 PTTYAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEETnlvedilgpelGWFPKEFVR 353
Cdd:smart00326   1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKE-----------GLFPSNYVE 56

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  437 IIRRSAVRELLDTEVNYVKLLAAICDGYLP------AMSKRIDIfspNSIRLIFSNITAIYKFQRKFLEALRR----GIE 506
Cdd:COG5422  483 IKRQEAIYEVIYTERDFVKDLEYLRDTWIKpleesnIIPENARR---NFIKHVFANINEIYAVNSKLLKALTNrqclSPI 559

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  507 QNQVAKVFLKMHKGFLCYSTYCNAYPRALIELETYDRV--KDAR--TILENCRESQNLAelpLSAHLLAPVQRICRYPLH 582
Cdd:COG5422  560 VNGIADIFLDYVPKFEPFIKYGASQPYAKYEFEREKSVnpNFARfdHEVERLDESRKLE---LDGYLTKPTTRLARYPLL 636

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  583 LNEIIKSalekgAKEGNDtdgaksagkttDYEqldvtelDIPDSQDTVNlalEAMRGITEAVNEGK-RHSETIARHQASF 661
Cdd:COG5422  637 LEEVLKF-----TDPDNP-----------DTE-------DIPKVIDMLR---EFLSRLNFESGKAEnRGDLFHLNQQLLF 690

                        250       260       270       280       290       300
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 24654698  662 QNfKGPPLHLHSARFFLQVDATRQKQNLWNSS------YTLFLFDNQLVYCKRDIIKRSH 715
Cdd:COG5422  691 KP-EYVNLGLNDEYRKIIFKGVLKRKAKSKTDgslrgdIQFFLLDNMLLFCKAKAVNKWR 749

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEEtnlvedilgpelGWFPKEFVRI 354
Cdd:cd11974   2 YAEALWDHVTMDDQELAFKAGDVIRVLEASNKDWWWGRNEDRE------------AWFPASFVRL 54

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEETNlvedilgPELGWFPKEFVRII 355
Cdd:cd11993   6 AQVIASYTATGPEQLTLAPGQLILIRKKNPGGWWEGELQARGKK-------RQIGWFPANYVKLL 63

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 24654698   293 VLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEETnlvedilgpelGWFP 348
Cdd:pfam00018   2 ALYDYTAQEPDELSFKKGDIIIVLEKSEDGWWKGRNKGGKE-----------GLIP 46

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24654698   696 LFLFDNQLVYCKRDIIKRSHfIYKGRIFLDRCRVVNVRDGKMFGHTIKNSLRIYSESRDKWYDFSFRSANRKHRFLSTL 774
Cdd:pfam00169  23 FVLFDGSLLYYKDDKSGKSK-EPKGSISLSGCEVVEVVASDSPKRKFCFELRTGERTGKRTYLLQAESEEERKDWIKAI 100

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 24654698    696 LFLFDNQLVYCKRDIIKRSHFiYKGRIFLDRCRVVNVRDGKMFGHtiKNSLRIYSESRDKWYdFSFRSANRKHRFLSTL 774
Cdd:smart00233  23 FVLFNSTLLYYKSKKDKKSYK-PKGSIDLSGCTVREAPDPDSSKK--PHCFEIKTSDRKTLL-LQAESEEEREKWVEAL 97

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24654698 293 VLYNFTAGGPQELGLERGMLIEILRKEVG-----PWWFGRIKKeetnlvedilgpELGWFPKEFV 352
Cdd:cd12058   4 ALYDYEASGEDELSLRRGDVVEVLSQDAAvsgddGWWAGKIRH------------RLGIFPANYV 56

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRK--EVGPWWFGRIKKEEtnlvedilgpelGWFPKEFVRI 354
Cdd:cd11842   1 KAVALYDFAGEQPGDLAFQKGDIITILKKsdSQNDWWTGRIGGRE------------GIFPANYVEL 55

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRKEVGP--WWFGRIKKEEtnlvedilgpelGWFPKEFV 352
Cdd:cd12142   1 YCRVLFDYNPVAPDELALKKGDVIEVISKETEDegWWEGELNGRR------------GFFPDNFV 53

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 292 EVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEEtnlvedilgpelGWFPKEFVR 353
Cdd:cd11856   3 VAIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVRKGDKE------------GWVPASYLE 52

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 290 YAEVLYNFTAGGPQ-ELGLERGMLIEILRK-----EVGPWWFGRIKKEETnlvedilgpelGWFPKEFVRI 354
Cdd:cd11771   1 FCRALYDFTPENPEmELSLKKGDIVAVLSKtdplgRDSEWWKGRTRDGRI-----------GWFPSNYVEV 60

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEEtnlvedilgpelGWFPKEFVRI 354
Cdd:cd11975   7 AEAVWDHVTMANRELAFKAGDVIKVLDASNKDWWWGQIDDEE------------GWFPASFVRL 58

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 294 LYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKeetnlvedilGPElGWFPKEFV 352
Cdd:cd11812   5 LYDYTANRSDELTIHRGDIIRVLYKDNDNWWFGSLVN----------GQQ-GYFPANYV 52

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRikkeetnlvediLGPELGWFPKEFVR 353
Cdd:cd11950   2 VRALYDFEALEDDELGFNSGDVIEVLDSSNPSWWKGR------------LHGKLGLFPANYVA 52

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRikkeetnlvediLGPELGWFPKEFVRI 354
Cdd:cd11874   2 CKVLFSYTPQNEDELELKVGDTIEVLGEVEEGWWEGK------------LNGKVGVFPSNFVKE 53

Second Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the second SH3 domain of Tks proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 286 YPTTYAevlynFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEEtnlvedilgpelGWFPKEFVRI 354
Cdd:cd12016   3 YITTQA-----YKAENEDEIGFETGVVVEVIQKNLDGWWKIRYQGKE------------GWAPATYLKK 54

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRKEVGP--WWFGRikkeetnlvediLGPELGWFPKEFVRI 354
Cdd:cd11875   1 KARVLFDYEAENEDELTLREGDIVTILSKDCEDkgWWKGE------------LNGKRGVFPDNFVEP 55

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIkkeetnlvedilGPELGWFPKEFVRI 354
Cdd:cd11782   2 ARAKYNFNADTGVELSFRKGDVITLTRRVDENWYEGRI------------GGRQGIFPVSYVQV 53

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWW 324
Cdd:cd11824   2 YSVLYDYTAQEDDELSISKGDVVAVIEKGEDGWW 35

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 294 LYNFTAGGPQELGLERGMLIEILRKEVGPWWFG----RIKKE-ETNLVEDI 339
Cdd:cd11969   5 LYDYRAKRSDELSFCKGALIHNVSKETGGWWKGdyggKVQHYfPSNYVEDV 55

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 291 AEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFgrikKEETNLVEdilgpelGWFPKEFV 352
Cdd:cd11804   2 AVAKHDFKATAEDELSFKKGSILKVLNMEDDPNWY----KAELDGKE-------GLIPKNYI 52

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 295 YNFTAGGPQELGLERGMLIEILRKEVGPWWfgrikkeetnlvEDILGPELGWFPKEFVR 353
Cdd:cd12060   8 FNFKQTNEDELSVCKGDIIYVTRVEEGGWW------------EGTLNGKTGWFPSNYVR 54

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRikkeetnlvedILGpELGWFPKEFVR 353
Cdd:cd11949   1 YVQALFDFDPQEDGELGFRRGDFIEVMDNSDPNWWKGA-----------CHG-QTGMFPRNYVT 52

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

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gi 24654698 290 YAEVLYNFTAGGPQELGLERGMLIEILRKEVGPWWFGRIKKEEtnlvedilgpelGWFPKEF 351
Cdd:cd11817   1 WAVALYDFTGETEEDLSFQRGDRILVTEHLDAEWSRGRLNGRE------------GIFPRAF 50