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 578835435  86 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVHKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                         90       100
                 ....*....|....*....|
gi 578835435 166 ADLFRLIAFYCISRDVLPFT 185
Cdd:cd10394   81 ADLFRLIAFYCISRDVLPFT 100

Domain present in VPS9; Domain present in yeast vacuolar sorting protein 9 and other proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578835435   648 FVDVEKIKVKFMTMQKmySPEKKVMLLLRVCKLIYTVMENNSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDP 727
Cdd:smart00167   1 FVEIEQIELKFLQLYK--SPSDKIKCLLRACKLIYTLLETQSGEVAGADDFLPVLIYVIIKCDPRDLLLNAEYMEEFLEP 78

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 578835435   728 SLLHGEGGYYLTSAYGALSLIKNFQEEQAARLLSSETRD 766
Cdd:smart00167  79 SLLTGEGGYYLTSLSAALALIKGLTEAHALPLSPEQELE 117

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 578835435  86 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVHKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                         90       100
                 ....*....|....*....|
gi 578835435 166 ADLFRLIAFYCISRDVLPFT 185
Cdd:cd10394   81 ADLFRLIAFYCISRDVLPFT 100

Domain present in VPS9; Domain present in yeast vacuolar sorting protein 9 and other proteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578835435   648 FVDVEKIKVKFMTMQKmySPEKKVMLLLRVCKLIYTVMENNSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDP 727
Cdd:smart00167   1 FVEIEQIELKFLQLYK--SPSDKIKCLLRACKLIYTLLETQSGEVAGADDFLPVLIYVIIKCDPRDLLLNAEYMEEFLEP 78

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 578835435   728 SLLHGEGGYYLTSAYGALSLIKNFQEEQAARLLSSETRD 766
Cdd:smart00167  79 SLLTGEGGYYLTSLSAALALIKGLTEAHALPLSPEQELE 117

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 578835435  787 FQNYLRVAFQEVNSGCTGKTLLVRPYITTEDVCQICAEKFKV-GDPEEYSLFLFV--DETWQQLAEDTYPQKIKAELHSR 863
Cdd:pfam00788   1 DDGVLKVYTEDGKPGTTYKTILVSSSTTAEEVIEALLEKFGLeDDPRDYVLVEVLerGGGERRLPDDECPLQIQLQWPRD 80

                          90
                  ....*....|..
gi 578835435  864 pqPHIFHFVYKR 875
Cdd:pfam00788  81 --ASDSRFLLRK 90

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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 578835435   102 LSEEEAAEVLQAQPPGIFLVHKSTKMQKK-VLSLRlpceFGAPLKEFAIKESTY-TFSLEGsGISFADLFRLIAFY 175
Cdd:smart00252   8 ISREEAEKLLKNEGDGDFLVRDSESSPGDyVLSVR----VKGKVKHYRIRRNEDgKFYLEG-GRKFPSLVELVEHY 78

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 578835435  86 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVHKSTKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 165
Cdd:cd10394    1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                         90       100
                 ....*....|....*....|
gi 578835435 166 ADLFRLIAFYCISRDVLPFT 185
Cdd:cd10394   81 ADLFRLIAFYCISRDVLPFT 100

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 578835435  86 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVHKSTKMQKKVLSLRLPC-EFGAPLKEFAIKESTYTFSLEGSGIS 164
Cdd:cd10339    1 LLERLLLTRPVWLQLQLNAAEAAHMLQTEPPGTFLVRKSNTRQCQVLCMRLPEaSGPAFVSEHYIKESPGGVSLEGSELM 80

                         90       100
                 ....*....|....*....|.
gi 578835435 165 FADLFRLIAFYCISRDVLPFT 185
Cdd:cd10339   81 FPDLFRLIAFYCHSRDILPFT 101

Ras-associating (RA) domain of Ras and Rab interactor (Rin) protein family; Family of Ras-interaction/interference (Rin) proteins, also known as Ras and Rab interactors, is composed of Rin1, Rin2, and Rin3, which have multifunctional domains, including SH2 and proline-rich domains in the N-terminal region, and RH, VPS9, and RA domains in the C-terminal region. 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. 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. The RA domains of Rin1, Rin2, and Rin3 are well conserved and they all have Ras binding characteristics.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578835435 788 QNYLRVAFQEVNSGC-TGKTLLVRPYITTEDVCQICAEKFKVGDPEEYSLFLFVDETWQQLAEDTYPQKIKAELHSRPQP 866
Cdd:cd01776    1 QGFLRVAVPDENNGSiVSKTLPVRPSMTAREVCKMIAHKFRVTNPQDYGLFLLVDGEEIQLEDNECPQLIKGELLATSKK 80

                         90
                 ....*....|.
gi 578835435 867 HiFHFVYKRIK 877
Cdd:cd01776   81 P-CYFAYKRID 90

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 578835435  86 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVHKSTKMQKKVLSLRLPCEFGAP-LKEFAIKESTYTFSLEGSGIS 164
Cdd:cd10393    1 LRERLLLTRPVWLQLRANAAAALHVLRTEPPGTFLVRKSNTRQCQALCVRLPEASGPSfVSSHYIQESPGGVSLEGSELT 80

                         90       100
                 ....*....|....*....|.
gi 578835435 165 FADLFRLIAFYCISRDVLPFT 185
Cdd:cd10393   81 FPDLVQLICAYCHTRDILLLP 101

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 578835435  651 VEKIKVKFMTMQKMYSPEKKVMLLLRVCKLIYTVMEN-NSGRMYGADDFLPVLTYVIAQCDMLELDTEIEYMMELLDPSL 729
Cdd:pfam02204   1 WEQAQQELKKLNEAKSPREKLKCLLRTCKLITEALSKsNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDL 80

                          90       100
                  ....*....|....*....|...
gi 578835435  730 LHGEGGYYLTSAYGALSLIKNFQ 752
Cdd:pfam02204  81 LSGEEGYYLTTLEAALEFIESLD 103

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 578835435 790 YLRVAFQEVNSGCTGKTLLVRPYITTEDVCQICAEKFKV-GDPEEYSLFLFVD--ETWQQLAEDTYPQKIKAElhSRPQP 866
Cdd:cd17043    1 VLKVYDDDLAPGSAYKSILVSSTTTAREVVQLLLEKYGLeEDPEDYSLYEVSEkqETERVLHDDECPLLIQLE--WGPQG 78

                 ....*....
gi 578835435 867 HIFHFVYKR 875
Cdd:cd17043   79 TEFRFVLKR 87

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 578835435   787 FQNYLRVAFQeVNSGCTGKTLLVRPYITTEDVCQICAEKFKV-GDPEEYSLFLFV-DETWQQLAEDTYPQKIKAELHsrP 864
Cdd:smart00314   1 DTFVLRVYVD-DLPGGTYKTLRVSSRTTARDVIQQLLEKFHLtDDPEEYVLVEVLpDGKERVLPDDENPLQLQKLWP--R 77

                           90
                   ....*....|.
gi 578835435   865 QPHIFHFVYKR 875
Cdd:smart00314  78 RGPNLRFVLRK 88

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 578835435  91 LHTHPIWLQLSLSEEEAAEVLQAQPP--GIFLVHKSTKMQKK-VLSLrlpcEFGAPLKEFAI----KESTYTFSLEGSGI 163
Cdd:cd10414    1 IHRSQPWFHHKISRDEAQRLIIQQGLvdGVFLVRDSQSNPRTfVLSM----SHGQKIKHFQIipveDDGELFHTLDDGHT 76

                         90       100
                 ....*....|....*....|....
gi 578835435 164 SFADLFRLIAFYCISRDVLPFTLK 187
Cdd:cd10414   77 RFTDLIQLVEFYQLNKGVLPCKLK 100

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 578835435  91 LHTHPIWLQLSLSEEEAAEVL--QAQPPGIFLVHKSTK-----------MQKKVLSLRLPCEfgaplkefaiKESTYTFS 157
Cdd:cd10413    1 IHRTQPWFHGRISREESQRLIgqQGLVDGVFLVRESQRnpqgfvlslchLQKVKHYLILPSE----------EEGRLYFS 70

                         90       100       110
                 ....*....|....*....|....*....|
gi 578835435 158 LEGSGISFADLFRLIAFYCISRDVLPFTLK 187
Cdd:cd10413   71 MDDGQTRFTDLLQLVEFHQLNRGILPCLLR 100

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578835435 102 LSEEEAAEVLQAQPPGIFLVHKStkMQKKV---LSLRLPcefGAPLkEFAIKESTYTFSLEGSGISFADLFRLIAFYCIS 178
Cdd:cd10382   17 LSVEEAHAKLKREPVGTFLIRDS--RQKNCffaLSVKMA---SGPV-SIRILFKAGKFSLDGSKESFDCLFKLLEHYVAS 90