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 568943597 235 SVAENGSLLGQPWYSGNCDRQSVERALLHFQKDGAYTVRLSSGPHSSQPFTLAVLLRGRVFNIPIRQLDGGHHYALGREG 314
Cdd:cd09929    1 SAEEEADLLPKEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 568943597 315 RNhEELFSSVAAMVQHYTKHPLPLVDGHSGNRGLTYLRFPTK 356
Cdd:cd09929   81 RG-EETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLLYAAG 121

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. 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 568943597 235 SVAENGSLLGQPWYSGNCDRQSVERALLHFQKDGAYTVRLSSGPHSSQPFTLAVLLRGRVFNIPIRQLDGGHHYALGREG 314
Cdd:cd09929    1 SAEEEADLLPKEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 568943597 315 RNhEELFSSVAAMVQHYTKHPLPLVDGHSGNRGLTYLRFPTK 356
Cdd:cd09929   81 RG-EETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLLYAAG 121

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597  247 WYSGNCDRQSVERALLHFQKDGAYTVRLSsgphSSQP--FTLAVLLRGRVFNIPIRQLDGGHHYALGREGrnheelFSSV 324
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRES----ESTPggYTLSVRDDGKVKHYKIQSTDNGGYYISGGVK------FSSL 70

                  ....*..
gi 568943597  325 AAMVQHY 331
Cdd:pfam00017  71 AELVEHY 77

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. 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 568943597 235 SVAENGSLLGQPWYSGNCDRQSVERALLHFQKDGAYTVRLSSGPHSSQPFTLAVLLRGRVFNIPIRQLDGGHHYALGREG 314
Cdd:cd09929    1 SAEEEADLLPKEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 568943597 315 RNhEELFSSVAAMVQHYTKHPLPLVDGHSGNRGLTYLRFPTK 356
Cdd:cd09929   81 RG-EETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLLYAAG 121

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597  247 WYSGNCDRQSVERALLHFQKDGAYTVRLSsgphSSQP--FTLAVLLRGRVFNIPIRQLDGGHHYALGREGrnheelFSSV 324
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRES----ESTPggYTLSVRDDGKVKHYKIQSTDNGGYYISGGVK------FSSL 70

                  ....*..
gi 568943597  325 AAMVQHY 331
Cdd:pfam00017  71 AELVEHY 77

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597 243 LGQPWYSGNCDRQSVERALLHFQKDGAYTVRLSSGPHSSqpFTLAVLLRGRVfnipirqldggHHYALGREGR-----NH 317
Cdd:cd09932    2 ESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSETDPNS--FAISFRAEGKI-----------KHCRIKQEGRlfvigTS 68

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 568943597 318 EelFSSVAAMVQHYTKHPLplvdghsgNRGlTYLRFP 354
Cdd:cd09932   69 Q--FESLVELVSYYEKHPL--------YRK-IKLRYP 94

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the Src non-receptor type tyrosine kinase family of proteins. The integration of receptor tyrosine kinase-induced RAS and Src42 signals by Connector eNhancer of KSR (CNK) as a two-component input is essential for RAF activation in Drosophila. Src42 is present in a wide variety of organisms including: California sea hare, pea aphid, yellow fever mosquito, honey bee, Panamanian leafcutter ant, and sea urchin. Src42 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 C-terminal tail. 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 568943597 245 QPWYSGNCDRQSVERALLHFQKD-GAYTVRLSSGPHSSqpFTLAVLLRGRVFNIPIRQLDGGHHYALGRegrnheELFSS 323
Cdd:cd10370    3 EPWYFGKIKRIEAEKKLLLPENEhGAFLIRDSESRHND--YSLSVRDGDTVKHYRIRQLDEGGFFIARR------TTFRT 74

                         90
                 ....*....|..
gi 568943597 324 VAAMVQHYTKHP 335
Cdd:cd10370   75 LQELVEHYSKDS 86

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 568943597 245 QPWYSGNCDRQSVERALLHFQ-KDGAYTVRLSSGPHSSqpFTLAVLLRGRVFNIPIRQLDGGHHYALGRegrnheELFSS 323
Cdd:cd10369    3 EPWFFGAIKRADAEKQLLYSEnQTGAFLIRESESQKGE--FSLSVLDGGVVKHYRIRRLDEGGFFLTRR------KTFST 74

                         90
                 ....*....|
gi 568943597 324 VAAMVQHYTK 333
Cdd:cd10369   75 LNEFVNYYTT 84

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 568943597 245 QPWYSGNCDRQSVERALLHfQKDGAYTVRLSSgphsSQP--FTLAVLLRGRVFNIPIRQLDGghhyalgREGRNHEELFS 322
Cdd:cd09937    3 MPWFHGKISREEAERLLQP-PEDGLFLVREST----NYPgdYTLCVSFEGKVEHYRVIYRNG-------KLTIDEEEYFE 70

                         90
                 ....*....|.
gi 568943597 323 SVAAMVQHYTK 333
Cdd:cd09937   71 NLIQLVEHYTK 81

N-terminal Src homology 2 (nSH2) 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, an internal 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 568943597 241 SLLGQPWYSGNCDRQSVERALlHFQKDGAYTVRLSSGPHSSqpFTLAVLLRGRVFNIPIRQLDGghhyalgREGRNHEEL 320
Cdd:cd09942    3 SLQEAEWYWGDISREEVNEKM-RDTPDGTFLVRDASTMKGD--YTLTLRKGGNNKLIKIFHRDG-------KYGFSDPLT 72

                         90
                 ....*....|.
gi 568943597 321 FSSVAAMVQHY 331
Cdd:cd09942   73 FNSVVELINYY 83

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597 243 LGQPWYSGNC--DRQSVERALLHFQK--DGAYTVRLSSGphSSQPFTLAVLLRGRVFNIPIRQLDGGHH--YALgregrN 316
Cdd:cd10341    2 FTEPWFHGKLgdGRDEAEKLLLEYCEggDGTFLVRESET--FVGDYTLSFWRNGKVQHCRIRSRQENGEkkYYL-----T 74

                         90       100
                 ....*....|....*....|
gi 568943597 317 HEELFSSVAAMVQHYTKHPL 336
Cdd:cd10341   75 DNLVFDSLYELIDYYRQNPL 94

C-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 its 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 568943597 247 WYSGNCDRQ-SVERALLHFQKDGAYTVRLSSGPHSSqpFTLAVLLRGRVFNIPIRQLDggHHYALGREGrnheELFSSVA 325
Cdd:cd10348    2 WLHGALDRNeAVEILKQKADADGSFLVRYSRRRPGG--YVLTLVYENHVYHFEIQNRD--DKWFYIDDG----PYFESLE 73

                         90
                 ....*....|
gi 568943597 326 AMVQHYTKHP 335
Cdd:cd10348   74 HLIEHYTQFA 83

Src homology 2 (SH2) domain found in the Vav3 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav3 preferentially activates RhoA, RhoG and, to a lesser extent, Rac1. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. VAV3 has been shown to interact with Grb2. 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. 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 568943597 244 GQPWYSGNCDRQSVERALLHfQKDGAYTVRLSSgpHSSQPFTLAVLLRGRVFNIPIRQLDGGHHYALGREgrnheelFSS 323
Cdd:cd10407    4 CQPWYAGAMERLQAETELIN-RVNSTYLVRHRT--KESGEYAISIKYNNEVKHIKILTRDGFFHIAENRK-------FKS 73

                         90       100       110
                 ....*....|....*....|....*....|....
gi 568943597 324 VAAMVQHYTKHPLplvdgHSGNRGL-TYLRFPTK 356
Cdd:cd10407   74 LMELVEYYKHHSL-----KEGFRSLdTTLQFPYK 102

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought to play a role in PDGF-receptor signaling and regulation of apoptosis. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHF contains four putative tyrosine phosphorylation sites and an 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 568943597 245 QPWYSGNCDRQSVErALLHFQKDGAYTVRLSSGPHSSqpftlavllrgrvFNIPIRQLDGGHHYALGREGRN------HE 318
Cdd:cd10392    1 QVWYHGAISRTDAE-NLLRLCKEASYLVRNSETSKND-------------FSLSLKSSQGFMHMKLSRTKEHkyvlgqNS 66

                         90       100
                 ....*....|....*....|
gi 568943597 319 ELFSSVAAMVQHYTKHPLPL 338
Cdd:cd10392   67 PPFSSVPEIIHHYASRKLPI 86

Src homology 2 domain found in SH2 domain-containing adapter proteins D (SHD); The expression of SHD is restricted to the brain. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a 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 568943597 245 QPWYSGNCDRQSVErALLHFQKDGAYTVRLSSGphSSQPFTLAvllrgrvfnipIRQLDGGHHYALGREGRN------HE 318
Cdd:cd10390    1 QPWFHGPLSRADAE-NLLSLCKEGSYLVRLSET--RPQDCSLS-----------LRSSQGFLHLKFARTRENqvvlgqHS 66

                         90       100
                 ....*....|....*....|
gi 568943597 319 ELFSSVAAMVQHYTKHPLPL 338
Cdd:cd10390   67 GPFPSVPELVLHYSSRPLPV 86

Src homology 2 (SH2) domain found in B lymphoid kinase (Blk); Blk is a member of the Src non-receptor type tyrosine kinase family of proteins. Blk is expressed in the B-cells. Unlike most other Src members Blk lacks cysteine residues in the SH4 domain that undergo palmitylation. Blk is required for the development of IL-17-producing gamma-delta T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny. Blk 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.

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gi 568943597 245 QPWYSGNCDRQSVERALLH-FQKDGAYTVRLSSGphSSQPFTLAV---LLRGRVF-NIPIRQLDGGHHYALGREGrnhee 319
Cdd:cd10371    3 EKWFFRTISRKDAERQLLApMNKAGSFLIRESES--NKGAFSLSVkdvTTQGEVVkHYKIRSLDNGGYYISPRIT----- 75

                         90
                 ....*....|....
gi 568943597 320 lFSSVAAMVQHYTK 333
Cdd:cd10371   76 -FPTLQALVQHYSK 88

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597 244 GQPWYSGNCDRQSVERALLHF-QKDGAYTVRLSSGPHSSqpFTLAVL----LRG-RVFNIPIRQLDGGHHYALGREGrnh 317
Cdd:cd10419    2 AEEWYFGKLGRKDAERQLLSFgNPRGTFLIRESETTKGA--YSLSIRdwddMKGdHVKHYKIRKLDNGGYYITTRAQ--- 76

                         90
                 ....*....|....*.
gi 568943597 318 eelFSSVAAMVQHYTK 333
Cdd:cd10419   77 ---FETLQQLVQHYSE 89

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. 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.

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gi 568943597 247 WYSGNCDRQSVERALLHFQKDGAYTVRLSSGphssqpftlavllRGRVFNIPIRQLDGGHHYALGREGRNHE---ELFSS 323
Cdd:cd10355    8 WYHGNLTRHAAEALLLSNGVDGSYLLRNSNE-------------GTGLFSLSVRAKDSVKHFHVEYTGYSFKfgfNEFSS 74

                         90
                 ....*....|...
gi 568943597 324 VAAMVQHYTKHPL 336
Cdd:cd10355   75 LQDFVKHFANQPL 87

Src homology 2 (SH2) domain found in Yes; Yes is a member of the Src non-receptor type tyrosine kinase family of proteins. Yes is the cellular homolog of the Yamaguchi sarcoma virus oncogene. In humans it is encoded by the YES1 gene which maps to chromosome 18 and is in close proximity to thymidylate synthase. A corresponding Yes pseudogene has been found on chromosome 22. YES1 has been shown to interact with Janus kinase 2, CTNND1,RPL10, and Occludin. Yes1 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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568943597 244 GQPWYSGNCDRQSVERALLH-FQKDGAYTVRLSSGPHSSqpFTLAVL----LRG-RVFNIPIRQLDGGHHYALGREGrnh 317
Cdd:cd10366    2 AEEWYFGKMGRKDAERLLLNpGNQRGIFLVRESETTKGA--YSLSIRdwdeVRGdNVKHYKIRKLDNGGYYITTRAQ--- 76

                         90
                 ....*....|....*..
gi 568943597 318 eelFSSVAAMVQHYTKH 334
Cdd:cd10366   77 ---FDTLQKLVKHYTEH 90