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 1886264310  86 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394     1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                          90
                  ....*....|....
gi 1886264310 166 ADLFRLIAFYCISR 179
Cdd:cd10394    81 ADLFRLIAFYCISR 94

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310  86 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394     1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                          90
                  ....*....|....
gi 1886264310 166 ADLFRLIAFYCISR 179
Cdd:cd10394    81 ADLFRLIAFYCISR 94

Vacuolar sorting protein 9 (VPS9) domain; This domain acts as a GDP-GTP exchange factor (GEF). It activates Rab GTPases by stimulating the release of GDP and allowing GTP to bind.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310 615 VEKIKVKFMTMQKMYSPEKKVMLLLRVCKLIYTVMEN-NSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDPSL 693
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90       100
                  ....*....|....*....|...
gi 1886264310 694 LHGEGGYYLTSAYGALSLIKNFQ 716
Cdd:pfam02204  81 LSGEEGYYLTTLEAALEFIESLD 103

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 1886264310  751 FQNYLRVAFqEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKV-GDPEEYSLFLFV-DETWQQLAEDTYPQKIKAELHsrP 828
Cdd:smart00314   1 DTFVLRVYV-DDLPGGTYKTLRVSSRTTARDVIQQLLEKFHLtDDPEEYVLVEVLpDGKERVLPDDENPLQLQKLWP--R 77

                           90
                   ....*....|.
gi 1886264310  829 QPHIFHFVYKR 839
Cdd:smart00314  78 RGPNLRFVLRK 88

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310  86 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394     1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                          90
                  ....*....|....
gi 1886264310 166 ADLFRLIAFYCISR 179
Cdd:cd10394    81 ADLFRLIAFYCISR 94

Src homology 2 (SH2) domain found in Ras and Rab interactor (RIN)-family; The RIN (AKA Ras interaction/interference) family is composed of RIN1, RIN2 and RIN3. These proteins have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs, and RIN3 specifically functions as a Rab31-GEF. 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 1886264310  86 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKKVLSLRLPC-EFGAPLKEFAIKESTYTFSLEGSGIS 164
Cdd:cd10339     1 LLERLLLTRPVWLQLQLNAAEAAHMLQTEPPGTFLVRKSNTRQCQVLCMRLPEaSGPAFVSEHYIKESPGGVSLEGSELM 80

                          90
                  ....*....|....*
gi 1886264310 165 FADLFRLIAFYCISR 179
Cdd:cd10339    81 FPDLFRLIAFYCHSR 95

Src homology 2 (SH2) domain found in Ras and Rab interactor 1 (RIN1)-like proteins; RIN1, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs). RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does. The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310  86 ILDRLLHTHPIWLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKKVLSLRLPCEFGAP-LKEFAIKESTYTFSLEGSGIS 164
Cdd:cd10393     1 LRERLLLTRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQALCVRLPEASGPSfVSSHYIQESPGGVSLEGSELT 80

                          90
                  ....*....|....*
gi 1886264310 165 FADLFRLIAFYCISR 179
Cdd:cd10393    81 FPDLVQLICAYCHTR 95

Ras-associating (RA) domain found in Ras and Rab interactor 3 (Rin3); Rin3, also termed Ras interaction/interference protein 3, is a RAS effector and a RAB5-activating guanine nucleotide exchange factor (GEF) specifically for GTPase Rab31. It functions as a negative regulator of mast cell responses to Stem Cell Factor (SCF). Rin3 contains the Vps9p-like guanine nucleotide exchange factor and Ras-association (RA) domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310 752 QNYLRVAFQEVnsGCTGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQPH 831
Cdd:cd16130     1 QDFISVSFLEP--GSNTRTLAIRPDTTAEDLCKQCAEKFEVLDPENYGLFVLVDGRCLQLADDALPHHIKSDLLKSEPRK 78

                  ....*....
gi 1886264310 832 IFHFVYKRI 840
Cdd:cd16130    79 DFHFLYKQL 87

Ras-associating (RA) domain found in Ras and Rab interactor 1 (Rin1); Rin1, also termed Ras inhibitor JC99, or Ras interaction/interference protein 1, is a downstream Ras effector that represents a unique class of Ras effector connected to two independent signaling pathways. The first effector pathway is the direct activation of RAB5-mediated endocytosis and the second pathway involves direct activation of ABL tyrosine kinase activity. Rin1 functions as a guanine nucleotide exchange factor (GEF) for RAB5 GTPases. The RAB5 GEF activity of Rin1 promotes early endosome fusion, an early event in transit to the lysosome. Rin1 binds the SH3 and SH2 domains of ABL proteins, ABL1 and ABL2, and activates their tyrosine kinase activity. Rin1 contains SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. The RA domain has the beta-grasp ubiquitin-like (Ubl) fold with low sequence similarity to ubiquitin; ubiquitin is a protein modifier in eukaryotes that is involved in various cellular processes including transcriptional regulation, cell cycle control, and DNA repair.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310 752 QNYLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELhsRPQPH 831
Cdd:cd17215     1 QNFLRVAYQDPSSGCTSKTLAVPPSATVADLNQLCATKFKVTQPETYGIFLYKEQGYQRLPPDALPQRIKAQL--KEKGS 78

                  ....*...
gi 1886264310 832 IFHFVYKR 839
Cdd:cd17215    79 TFYFVYQR 86

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310 751 FQNYLRVAFQEVNSGCTGKTLLVRPYVTTEDVCQLCAEKFKV-GDPEEYSLFLFV--DETWQQLAEDTYPQKIKAELHSR 827
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTYKTILVSSSTTAEEVIEALLEKFGLeDDPRDYVLVEVLerGGGERRLPDDECPLQIQLQWPRD 80

                          90
                  ....*....|..
gi 1886264310 828 pqPHIFHFVYKR 839
Cdd:pfam00788  81 --ASDSRFLLRK 90

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 1886264310  97 WLQLSLSEEEAAQVLRSQPPGIFLVRKSTKMQKK-VLSLRlpCEFGAPlKEFAIKESTYTFSLEG-SGISFADLFRLIAF 174
Cdd:cd00173     2 WFHGSISREEAERLLRGKPDGTFLVRESSSEPGDyVLSVR--SGDGKV-KHYLIERNEGGYYLLGgSGRTFPSLPELVEH 78

                  .
gi 1886264310 175 Y 175
Cdd:cd00173    79 Y 79

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310  91 LHTHPIWLQLSLSEEEAAQVLRSQ--PPGIFLVRKS-TKMQKKVLSLRlpceFGAPLKEFAI----KESTYTFSLEGSGI 163
Cdd:cd09944     1 IHRSQPWFHGGISRDEAARLIRQQglVDGVFLVRESqSNPGAFVLSLK----HGQKIKHYQIipieDEGQWYFTLDDGVT 76

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1886264310 164 SFADLFRLIAFYCISRppssdGVCPASRQLCLINGV 199
Cdd:cd09944    77 KFYDLLQLVEFYQLNA-----GSLPTRLKHYCTRVA 107

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1886264310  91 LHTHPIWLQLSLSEEEAAQVLRSQPP--GIFLVRKSTKMQKK-VLSLrlpcEFGAPLKEFAI----KESTYTFSLEGSGI 163
Cdd:cd10414     1 IHRSQPWFHHKISRDEAQRLIIQQGLvdGVFLVRDSQSNPRTfVLSM----SHGQKIKHFQIipveDDGELFHTLDDGHT 76

                          90       100
                  ....*....|....*....|....*
gi 1886264310 164 SFADLFRLIAFYCISRppssdGVCP 188
Cdd:cd10414    77 RFTDLIQLVEFYQLNK-----GVLP 96

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 1886264310  91 LHTHPIWLQLSLSEEEAAQVLRSQP--PGIFLVRKSTK-----------MQKKVLSLRLPCEfgaplkefaiKESTYTFS 157
Cdd:cd10413     1 IHRTQPWFHGRISREESQRLIGQQGlvDGVFLVRESQRnpqgfvlslchLQKVKHYLILPSE----------EEGRLYFS 70

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1886264310 158 LEGSGISFADLFRLIAFYCISRppssdGVCPASRQLCLIN 197
Cdd:cd10413    71 MDDGQTRFTDLLQLVEFHQLNR-----GILPCLLRHCCTR 105