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 442615826  1322 IANLLWRLQEAELPLDKLELFLCVISTVFDAT-GCPRGQQLGADDFLPVLVYVVAKCGFVGAEIEAEFMWGLLQPTLLNG 1400
Cdd:pfam02204    4 AQQELKKLNEAKSPREKLKCLLRTCKLITEALsKSNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDLLSG 83

                           90       100
                   ....*....|....*....|
gi 442615826  1401 EPGYYLTALCSAVQVLKTFM 1420
Cdd:pfam02204   84 EEGYYLTTLEAALEFIESLD 103

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 442615826  1322 IANLLWRLQEAELPLDKLELFLCVISTVFDAT-GCPRGQQLGADDFLPVLVYVVAKCGFVGAEIEAEFMWGLLQPTLLNG 1400
Cdd:pfam02204    4 AQQELKKLNEAKSPREKLKCLLRTCKLITEALsKSNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDLLSG 83

                           90       100
                   ....*....|....*....|
gi 442615826  1401 EPGYYLTALCSAVQVLKTFM 1420
Cdd:pfam02204   84 EEGYYLTTLEAALEFIESLD 103

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826   1335 PLDKLELFLCVISTVFDATGCPRGQQLGADDFLPVLVYVVAKCGFVGAEIEAEFMWGLLQPTLLNGEPGYYLTALCSAVQ 1414
Cdd:smart00167   18 PSDKIKCLLRACKLIYTLLETQSGEVAGADDFLPVLIYVIIKCDPRDLLLNAEYMEEFLEPSLLTGEGGYYLTSLSAALA 97

                    ....*
gi 442615826   1415 VLKTF 1419
Cdd:smart00167   98 LIKGL 102

SH2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826   225 WFLPGIQRSGAVHLLQ-GKEEGTFIVRGS-SQPNTMAVSVRLPQDtgpyIEHYLIQSHDNVLSLESSRFTFGSIPSLIAH 302
Cdd:pfam00017    1 WYHGKISRQEAERLLLnGKPDGTFLVRESeSTPGGYTLSVRDDGK----VKHYKIQSTDNGGYYISGGVKFSSLAELVEH 76

                   .
gi 442615826   303 Y 303
Cdd:pfam00017   77 Y 77

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 442615826   1444 VLRVIIPDECNGslQTRTLPVRPHTTTREVCRIIAHKARIT-NPQDYALF-KLVDGEETLLTDAECPQDARLAAKGKHCM 1521
Cdd:smart00314    4 VLRVYVDDLPGG--TYKTLRVSSRTTARDVIQQLLEKFHLTdDPEEYVLVeVLPDGKERVLPDDENPLQLQKLWPRRGPN 81

                    ...
gi 442615826   1522 LAY 1524
Cdd:smart00314   82 LRF 84

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 442615826  1322 IANLLWRLQEAELPLDKLELFLCVISTVFDAT-GCPRGQQLGADDFLPVLVYVVAKCGFVGAEIEAEFMWGLLQPTLLNG 1400
Cdd:pfam02204    4 AQQELKKLNEAKSPREKLKCLLRTCKLITEALsKSNRDESLGADDLLPILIYVLIRANPPNLYSNLQFISEFRDPDLLSG 83

                           90       100
                   ....*....|....*....|
gi 442615826  1401 EPGYYLTALCSAVQVLKTFM 1420
Cdd:pfam02204   84 EEGYYLTTLEAALEFIESLD 103

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 442615826  225 WFLPGIQRSGAVHLLQGKEEGTFIVRGS-SQPNTMAVSVRLPQDTgpyIEHYLIQSHDNVLSL-ESSRFTFGSIPSLIAH 302
Cdd:cd00173     2 WFHGSISREEAERLLRGKPDGTFLVRESsSEPGDYVLSVRSGDGK---VKHYLIERNEGGYYLlGGSGRTFPSLPELVEH 78

                  .
gi 442615826  303 Y 303
Cdd:cd00173    79 Y 79

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 442615826  214 LMERLLVTHPMWFLPGIQRSGAVHLLQGKEEGTFIVRGSSQPNTMAVSVRLPQDTGPYIEHYLIQSHDNVLSLESSRFTF 293
Cdd:cd10394     1 ILDRLLHTHPIWLQLSLSEEEAAEVLQAQPPGIFLVRKSSKMQKKVLSLRLPCEFGAPLKEFAIKESTYTFSLEGSGISF 80

                          90
                  ....*....|....*...
gi 442615826  294 GSIPSLIAHYAQCCDELP 311
Cdd:cd10394    81 ADLFRLIAFYCISRDVLP 98

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 442615826    225 WFLPGIQRSGAVHLLQGKEEGTFIVRGSSQ-PNTMAVSVRLPQDtgpyIEHYLIQSH-DNVLSLESSRfTFGSIPSLIAH 302
Cdd:smart00252    3 WYHGFISREEAEKLLKNEGDGDFLVRDSESsPGDYVLSVRVKGK----VKHYRIRRNeDGKFYLEGGR-KFPSLVELVEH 77

                    .
gi 442615826    303 Y 303
Cdd:smart00252   78 Y 78

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
                  ....*....|....*....|....*....|....*....|....*....|..
gi 442615826 1458 QTRTLPVRPHTTTREVCRIIAHKARITNPQDYALFKLVDGEETLLTDAECPQ 1509
Cdd:cd16130    14 NTRTLAIRPDTTAEDLCKQCAEKFEVLDPENYGLFVLVDGRCLQLADDALPH 65

Src homology 2 (SH2) domain found in Ras and Rab interactor 3 (RIN3)-like proteins; RIN3, 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. RIN3 stimulated the formation of GTP-bound Rab31, a Rab5-subfamily GTPase, and formed enlarged vesicles and tubular structures, where it colocalized with Rab31. Transferrin appeared to be transported partly through the RIN3-positive vesicles to early endosomes. RIN3 interacts via its Pro-rich domain with amphiphysin II, which contains SH3 domain and participates in receptor-mediated endocytosis. RIN3, a Rab5 and Rab31 GEF, plays an important role in the transport pathway from plasma membrane to early endosomes. Mutations in the region between the SH2 and RH domain of RIN3 specifically abolished its GEF action on Rab31, but not Rab5. RIN3 was also found to partially translocate the cation-dependent mannose 6-phosphate receptor from the trans-Golgi network to peripheral vesicles and that this is dependent on its Rab31-GEF activity. These data indicate that RIN3 specifically acts as a GEF for Rab31. 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 442615826  214 LMERLLVTHPMWFLPGIQRSGAVHLLQGKEEGTFIVRGSSQPNTMAVSVRLP-QDTGPYIEHYLIQSHDNVLSLESSRFT 292
Cdd:cd10395     1 ILEKLIKTCPVWLQLGMNQAEAARILHKEVAGMFLVRRDSNSKQMVLCVHFPsNESSAEVLEYPIKEEKSILYLEGSVLV 80

                          90
                  ....*....|....*....
gi 442615826  293 FGSIPSLIAHYAQCCDELP 311
Cdd:cd10395    81 FEDIFKLIAFYCVSRDLLP 99

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQ--GKEEGTFIVRGS-SQPNTMAVSVRLPQDT-GPYIEHYLIQSHDNVLSLESSRFTFGSIPSLI 300
Cdd:cd09933     5 WFFGKIKRKDAEKLLLapGNPRGTFLIRESeTTPGAYSLSVRDGDDArGDTVKHYRIRKLDNGGYYITTRATFPTLQELV 84

                          90
                  ....*....|....*..
gi 442615826  301 AHYAQCCDELPVQLMLP 317
Cdd:cd09933    85 QHYSKDADGLCCRLTVP 101

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  222 HPM-WFLPGIQRSGAVHLLQGKEEGTFIVRGssqpntmavSVRLPQD------TGPYIEHYLIQSHDNVLSLESSRFtFG 294
Cdd:cd09937     1 SLMpWFHGKISREEAERLLQPPEDGLFLVRE---------STNYPGDytlcvsFEGKVEHYRVIYRNGKLTIDEEEY-FE 70

                          90       100
                  ....*....|....*....|....*
gi 442615826  295 SIPSLIAHYAQCCDELPVQLMLPRV 319
Cdd:cd09937    71 NLIQLVEHYTKDADGLCTRLVKPKV 95

Ras-associating (RA) domain found in Ras and Rab interactor 2 (Rin2); Rin2, also termed Ras association domain family 4, or Ras inhibitor JC265, or Ras interaction/interference protein 2, is a Rab5 GDP/GTP exchange factor with the Vps9p-like guanine nucleotide exchange factor and Ras-association (RA) domains. Rin2 connects three GTPases, R-Ras, Rab5 and Rac1, to promote endothelial cell adhesion through the regulation of integrin internalization and Rac1 activation. Rin2 is involved in the regulation of Rab5-mediated early endocytosis. The deficiency of Rin2 can cause the RIN2 syndrome, an autosomal recessive connective tissue disorder.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 442615826 1445 LRVIIpDECNGSLQTRTLPVRPHTTTREVCRIIAHKARITNPQDYALFKLVDGEETLLTDAECPQ 1509
Cdd:cd16131     5 LRVAF-QEVNSGCTAKTLLVRPYTTTEEVCQLCAQKFKVQDPENYSLFLLIDDTWQQLAEDTYPQ 68

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQGKEEGTFIVRGSSQPN-TMAVSVRlpQDTGPYieHYLIQSHDNVLSLESSR---FTFGSIPSLI 300
Cdd:cd09923     2 WYWGGITRYEAEELLAGKPEGTFLVRDSSDSRyLFSVSFR--TYGRTL--HARIEYSNGRFSFDSSDpsvPRFPCVVELI 77

                  ....
gi 442615826  301 AHYA 304
Cdd:cd09923    78 EHYV 81

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 442615826 1444 VLRVIIPDECNGSlQTRTLPVRPHTTTREVCRIIAHKARIT-NPQDYALFKLVDGEET--LLTDAECPQDARLAAK 1516
Cdd:cd17043     1 VLKVYDDDLAPGS-AYKSILVSSTTTAREVVQLLLEKYGLEeDPEDYSLYEVSEKQETerVLHDDECPLLIQLEWG 75

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQGKEEGTFIVRGSSQPNTMAVSVRLPQDtgpyIEHYLIQSHDNVLSLESSRFTFGSIPSLIAHYA 304
Cdd:cd09930     8 WLVGDINRTQAEELLRGKPDGTFLIRESSTQGCYACSVVCNGE----VKHCVIYKTETGYGFAEPYNLYESLKELVLHYA 83

                          90
                  ....*....|....*...
gi 442615826  305 -----QCCDELPVQLMLP 317
Cdd:cd09930    84 hnsleQHNDSLTVTLAYP 101

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in the hematopoietic cells, in neural tissues, liver, and adipose tissue. There are two alternatively spliced forms of Lyn. Lyn plays an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation, triggering a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phospholipase C2 (PLC2) and phosphatidyl inositol-3 kinase. These kinases play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FC RIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1 which further down modulate signaling pathways, attenuate cell activation and can mediate tolerance. Lyn also plays a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1) leading to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. It is the primary Src family member involved in signaling downstream of the B cell receptor. Lyn plays an unusual, 2-fold role in B cell receptor signaling; it is essential for initiation of signaling but is also later involved in negative regulation of the signal. Lyn 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 442615826  225 WFLPGIQRSGAVH--LLQGKEEGTFIVRGS-SQPNTMAVSVR-LPQDTGPYIEHYLIQSHDNVLSLESSRFTFGSIPSLI 300
Cdd:cd10364     5 WFFKDITRKDAERqlLAPGNSAGAFLIRESeTLKGSYSLSVRdYDPQHGDVIKHYKIRSLDNGGYYISPRITFPCISDMI 84

                          90
                  ....*....|
gi 442615826  301 AHYAQCCDEL 310
Cdd:cd10364    85 KHYQKQSDGL 94

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQGK-EEGTFIVRGSSQPNTMAVSV--RLPQDTGPYIEHYLIQSH-DNVLSLeSSRFTFGSIPSLI 300
Cdd:cd10399     8 WFAGNISRSQSEQLLRQKgKEGAFMVRNSSQVGMYTVSLfsKAVNDKKGTVKHYHVHTNaENKLYL-AENYCFDSIPKLI 86

                  ....*
gi 442615826  301 aHYAQ 305
Cdd:cd10399    87 -HYHQ 90

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 442615826  220 VTHPMWFLPGIQRSGAVHLLQGKEEGTFIVRGSSQPNTM-AVSVRLPQDtgpyIEHYLI-QSHDNVLSLESSRFtFGSIP 297
Cdd:cd09940     2 LSEFLWFVGEMERDTAENRLENRPDGTYLVRVRPQGETQyALSIKYNGD----VKHMKIeQRSDGLYYLSESRH-FKSLV 76

                  ....*.
gi 442615826  298 SLIAHY 303
Cdd:cd09940    77 ELVNYY 82

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQGKEEGTFIVRGS-SQPNTMAVSVRlpQDTGPYieHYLIQ--SHDNVLSLESSRFTFgsIPSLIA 301
Cdd:cd09935     5 WYHGPISRNAAEYLLSSGINGSFLVRESeSSPGQYSISLR--YDGRVY--HYRISedSDGKVYVTQEHRFNT--LAELVH 78

                          90
                  ....*....|....*.
gi 442615826  302 HYAQCCDELPVQLMLP 317
Cdd:cd09935    79 HHSKNADGLITTLRYP 94

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQGKEEGTFIVRGS-SQPNT--MAVSVRLPQ--------DTGPYIE---HYLIQSHDNVLSLE--S 288
Cdd:cd09927     5 WYKPNISRDQAIALLKDKPPGTFLVRDStTYKGAygLAVKVATPPpgvnpfeaKGDPESElvrHFLIEPSPKGVKLKgcP 84

                          90       100
                  ....*....|....*....|....*....
gi 442615826  289 SRFTFGSIPSLIAHYAQCCDELPVQLMLP 317
Cdd:cd09927    85 NEPVFGSLSALVYQHSITPLALPCKLRIP 113

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVH--LLQGKEEGTFIVRGS-SQPNTMAVSVRlpqdTGPYIEHYLIQSHDNVLSLESSRFTFGSIPSLIA 301
Cdd:cd10369     5 WFFGAIKRADAEKqlLYSENQTGAFLIRESeSQKGEFSLSVL----DGGVVKHYRIRRLDEGGFFLTRRKTFSTLNEFVN 80

                          90
                  ....*....|....*.
gi 442615826  302 HYAQCCDELPVQLMLP 317
Cdd:cd10369    81 YYTTTSDGLCVKLGKP 96

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 442615826  225 WFLPGIQRSGAVHLL--QGKEEGTFIVRGS-SQPNTMAVSVRLPQDtgpyIEHYLIQSH-DNVLSLESSRFTFGSIPSLI 300
Cdd:cd10347     3 WYHGKISREVAEALLlrEGGRDGLFLVREStSAPGDYVLSLLAQGE----VLHYQIRRHgEDAFFSDDGPLIFHGLDTLI 78

                  ...
gi 442615826  301 AHY 303
Cdd:cd10347    79 EHY 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLL-QGKEEGTFIVRGS-SQPNTMAVSVRlpqdTGPYIEHYLIQSHDNVLSLESSRfTFGSIPSLIAH 302
Cdd:cd10354     2 WFHGKISREEAYNMLvKVGGPGSFLVRESdNTPGDYSLSFR----VNEGIKHFKIIPTGNNQFMMGGR-YFSSLDDVIDR 76

                  .
gi 442615826  303 Y 303
Cdd:cd10354    77 Y 77

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVH--LLQGKEEGTFIVRGS-SQPNTMAVSVRLPQDT-GPYIEHYLIQSHDNVLSLESSRFTFGSIPSLI 300
Cdd:cd10418     5 WYFGKLGRKDAERqlLSFGNPRGTFLIRESeTTKGAYSLSIRDWDDMkGDHVKHYKIRKLDNGGYYITTRAQFETLQQLV 84

                          90
                  ....*....|....*..
gi 442615826  301 AHYAQCCDELPVQLMLP 317
Cdd:cd10418    85 QHYSERAAGLCCRLVVP 101

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain 1, F1 sub-domain, found in Myosin-VIIa, Myosin-VIIb, and similar proteins; This family includes two nontraditional members of the myosin superfamily, myosin-VIIa and myosin-VIIb. Myosin-VIIa, also termed myosin-7a (Myo7a), has been implicated in the structural organization of hair bundles at the apex of sensory hair cells (SHCs) where it serves mechanotransduction in the process of hearing and balance. Mutations in the MYO7A gene may be associated with Usher Syndrome type 1B (USH1B) and nonsyndromic hearing loss (DFNB2, DFNA11). Myosin-VIIb, also termed myosin-7b (Myo7b), is a high duty ratio motor adapted for generating and maintaining tension. It associates with harmonin and ANKS4B to form a stable ternary complex for anchoring microvilli tip-link cadherins. Like other unconventional myosins, myosin-VII is composed of a conserved motor head, a neck region and a tail region containing two MyTH4 domains, a SH3 domain, and two FERM domains. The FERM domain is made up of three sub-domains, F1, F2, and F3. The family corresponds to the F1 sub-domain of the first FERM domain, which is also called the N-terminal ubiquitin-like structural domain of the FERM domain (FERM_N).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 442615826 1444 VLRVIIPDEcngslQTRTLPVRPHTTTREVCRIIAHKARITNPQDYALF-KLVDGEETLLTDAECPQDA 1511
Cdd:cd17092     3 MLPVTFMDG-----STKTVEVDSATTARELCRQLAEKLGLKDTFGFSLYiALFDKVSSLGSGTDHVMDA 66

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQ--GKEEGTFIVRGS-SQPNTMAVSVRLPQDT-GPYIEHYLIQSHDNVLSLESSRFTFGSIPSLI 300
Cdd:cd10368     5 WYFGKLGRKDAERQLLsfGNPRGTFLIRESeTTKGAYSLSIRDWDDMkGDHVKHYKIRKLDNGGYYITTRAQFETLQQLV 84

                          90
                  ....*....|....*..
gi 442615826  301 AHYAQCCDELPVQLMLP 317
Cdd:cd10368    85 QHYSETANGLCKVLIVT 101

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 442615826  225 WFLPGIQRSGAVHLLQ--GKEEGTFIVRGS-SQPNTMAVSVRLPQDT-GPYIEHYLIQSHDNVLSLESSRFTFGSIPSLI 300
Cdd:cd10419     5 WYFGKLGRKDAERQLLsfGNPRGTFLIRESeTTKGAYSLSIRDWDDMkGDHVKHYKIRKLDNGGYYITTRAQFETLQQLV 84

                          90
                  ....*....|....*.
gi 442615826  301 AHYAQCCDELPVQLML 316
Cdd:cd10419    85 QHYSEKADGLCFNLTV 100