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 1958676751  794 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 873
Cdd:cd09927      1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1958676751  874 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 910
Cdd:cd09927     80 LKGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

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 1958676751  794 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 873
Cdd:cd09927      1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1958676751  874 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 910
Cdd:cd09927     80 LKGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958676751   933 QGAACNVWYLNSVEMESLTGHQAVQKALNMTLVQEPPPVSTV--VHFKVSAQGITLTDNQRKlFFRRHYPVSSVIFCALD 1010
Cdd:smart00462    2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPqkVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVG 80

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|.
gi 1958676751  1011 PQDrkwikdgpsSKVFGFVARKQGSaTDNVCHLF--AEHDPEQPASAIVNF 1059
Cdd:smart00462   81 PDD---------LDVFGYIARDPGS-SRFACHVFrcEKAAEDIALAIGQAF 121

SH2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958676751  798 WYKADISREQAIAMLK-DKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkagdlsNELVRHFLIECTPKGVRLkg 876
Cdd:pfam00017    1 WYHGKISRQEAERLLLnGKPDGTFLVRESESTPGGYTL---------SVRD---------DGKVKHYKIQSTDNGGYY-- 60

                           90
                   ....*....|....
gi 1958676751  877 CSNEPYFGSLTALV 890
Cdd:pfam00017   61 ISGGVKFSSLAELV 74

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 1958676751  794 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 873
Cdd:cd09927      1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1958676751  874 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 910
Cdd:cd09927     80 LKGCPNEPVFGSLSALVYQHSITPLALPCKLRIPDRD 116

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958676751   933 QGAACNVWYLNSVEMESLTGHQAVQKALNMTLVQEPPPVSTV--VHFKVSAQGITLTDNQRKlFFRRHYPVSSVIFCALD 1010
Cdd:smart00462    2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPqkVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVG 80

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|.
gi 1958676751  1011 PQDrkwikdgpsSKVFGFVARKQGSaTDNVCHLF--AEHDPEQPASAIVNF 1059
Cdd:smart00462   81 PDD---------LDVFGYIARDPGS-SRFACHVFrcEKAAEDIALAIGQAF 121

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 1958676751   798 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRlkGC 877
Cdd:smart00252    3 WYHGFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRV------------------KGKVKHYRIRRNEDGKF--YL 62

                            90       100
                    ....*....|....*....|.
gi 1958676751   878 SNEPYFGSLTALVCQHSITPL 898
Cdd:smart00252   63 EGGRKFPSLVELVEHYQKNSL 83

SH2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958676751  798 WYKADISREQAIAMLK-DKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkagdlsNELVRHFLIECTPKGVRLkg 876
Cdd:pfam00017    1 WYHGKISRQEAERLLLnGKPDGTFLVRESESTPGGYTL---------SVRD---------DGKVKHYKIQSTDNGGYY-- 60

                           90
                   ....*....|....
gi 1958676751  877 CSNEPYFGSLTALV 890
Cdd:pfam00017   61 ISGGVKFSSLAELV 74

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 1958676751  798 WYKADISREQAIAMLKDKAPGSFIVRDShSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRLKgc 877
Cdd:cd09930      8 WLVGDINRTQAEELLRGKPDGTFLIRES-STQGCYACSVVC------------------NGEVKHCVIYKTETGYGFA-- 66

                           90       100
                   ....*....|....*....|....
gi 1958676751  878 snEPY--FGSLTALVCQHSITPLA 899
Cdd:cd09930     67 --EPYnlYESLKELVLHYAHNSLE 88

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 1958676751  798 WYKADISREQAIAML-KDKAPGSFIVRDSHSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRLKG 876
Cdd:cd10354      2 WFHGKISREEAYNMLvKVGGPGSFLVRESDNTPGDYSLSFRV------------------NEGIKHFKIIPTGNNQFMMG 63

                           90
                   ....*....|....
gi 1958676751  877 csnEPYFGSLTALV 890
Cdd:cd10354     64 ---GRYFSSLDDVI 74

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of adapter proteins that negatively regulate cellular signaling initiated by tyrosine kinases. It has a myristylated N-terminus, SH3 and SH2 domains with high homology to Src family tyrosine kinases, and a unique C-terminal tail, which is important for c-Cbl binding. SLAP negatively regulates platelet-derived growth factor (PDGF)-induced mitogenesis in fibroblasts and regulates F-actin assembly for dorsal ruffles formation. c-Cbl mediated SLAP inhibition towards actin remodeling. Moreover, SLAP enhanced PDGF-induced c-Cbl phosphorylation by SFK. In contrast, SLAP mitogenic inhibition was not mediated by c-Cbl, but it rather involved a competitive mechanism with SFK for PDGF-receptor (PDGFR) association and mitogenic signaling. Accordingly, phosphorylation of the Src mitogenic substrates Stat3 and Shc were reduced by SLAP. Thus, we concluded that SLAP regulates PDGFR signaling by two independent mechanisms: a competitive mechanism for PDGF-induced Src mitogenic signaling and a non-competitive mechanism for dorsal ruffles formation mediated by c-Cbl. SLAP is a hematopoietic adaptor containing Src homology (SH)3 and SH2 motifs and a unique carboxy terminus. Unlike c-Src, SLAP lacks a tyrosine kinase domain. Unlike c-Src, SLAP does not impact resorptive function of mature osteoclasts but induces their early apoptosis. SLAP negatively regulates differentiation of osteoclasts and proliferation of their precursors. Conversely, SLAP decreases osteoclast death by inhibiting activation of caspase 3. 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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958676751  798 WYKADISREQA--IAMLKDKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkAGDLSNELVRHFLIECTPKG 871
Cdd:cd10344     12 WLFEGLSREKAeeLLMLPGNQVGSFLIRESETRRGCYSL---------SVRH----RGSQSRDSVKHYRIFRLDNG 74

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. 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 1958676751  798 WYKADISREQAIAMLKDKAP-GSFIVRDShSFRGAYGLA--MKVATPPpsvlhlnkkagdlsneLVRHFLIECTPKG--- 871
Cdd:cd09934      8 WYVGDMSRQRAESLLKQEDKeGCFVVRNS-STKGLYTVSlfTKVPGSP----------------HVKHYHIKQNARSefy 70

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 1958676751  872 VRLKGCsnepyFGSLTALVCQHSITPLALPCKLLIP 907
Cdd:cd09934     71 LAEKHC-----FETIPELINYHQHNSGGLATRLKYP 101

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of the Tec protein tyrosine kinase Btk is expressed in bone marrow, spleen, all hematopoietic cells except T lymphocytes and plasma cells where it plays a crucial role in B cell maturation and mast cell activation. Btk has been shown to interact with GNAQ, PLCG2, protein kinase D1, B-cell linker, SH3BP5, caveolin 1, ARID3A, and GTF2I. 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. Btk is implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). 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 and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. 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. Two tyrosine phosphorylation (pY) sites have been identified in Btk: one located in the activation loop of the catalytic domain which regulates the transition between open (active) and closed (inactive) states and the other in its SH3 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
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1958676751  798 WYKADISREQAIAMLK-DKAPGSFIVRDShSFRGAYGLAMkvatpppsvlhLNKKAGDLSNeLVRHFLIECTPKG 871
Cdd:cd10397      8 WYSKNMTRSQAEQLLKqEGKEGGFIVRDS-SKAGKYTVSV-----------FAKSAGDPQG-VIRHYVVCSTPQS 69

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and SLAM-associated protein (SAP); The SH2-containing inositol-5'-phosphatase, SHIP (also called SHIP1/SHIP1a), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, SHIP dampens down PIP3 mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. PIP3 recruits lipid-binding pleckstrin homology(PH) domain-containing proteins to the inner wall of the plasma membrane and activates them. PH domain-containing downstream effectors include the survival/proliferation enhancing serine/threonine kinase, Akt (protein kinase B), the tyrosine kinase, Btk, the regulator of protein translation, S6K, and the Rac and cdc42 guanine nucleotide exchange factor, Vav. SHIP is believed to act as a tumor suppressor during leukemogenesis and lymphomagenesis, and may play a role in activating the immune system to combat cancer. SHIP contains an N-terminal SH2 domain, a centrally located phosphatase domain that specifically hydrolyzes the 5'-phosphate from PIP3, PI-4,5-P2 and inositol-1,3,4,5- tetrakisphosphate (IP4), a C2 domain, that is an allosteric activating site when bound by SHIP's enzymatic product, PI-3,4-P2; 2 NPXY motifs that bind proteins with a phosphotyrosine binding (Shc, Dok 1, Dok 2) or an SH2 (p85a, SHIP2) domain; and a proline-rich domain consisting of four PxxP motifs that bind a subset of SH3-containing proteins including Grb2, Src, Lyn, Hck, Abl, PLCg1, and PIAS1. The SH2 domain of SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule, Cas, c-Cbl, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs). The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX(V/I), which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. 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
                   ....*....|....*....|....*....|....*....|.
gi 1958676751  798 WYKADISREQAIAML----KDkapGSFIVRDSHSFRGAYGL 834
Cdd:cd10343      5 WYHGNITRSKAEELLskagKD---GSFLVRDSESVSGAYAL 42

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 1958676751  798 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKvatpppsvlhlnkkagdlSNELVRHFLIECTPKGVRLkgC 877
Cdd:cd09935      5 WYHGPISRNAAEYLLSSGINGSFLVRESESSPGQYSISLR------------------YDGRVYHYRISEDSDGKVY--V 64

                           90       100       110
                   ....*....|....*....|....*....|
gi 1958676751  878 SNEPYFGSLTALVCQHSITPLALPCKLLIP 907
Cdd:cd09935     65 TQEHRFNTLAELVHHHSKNADGLITTLRYP 94

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

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gi 1958676751  795 SKFWYKADISREQAIAMLKDKA--PGSFIVRDSHSFRGAYGLAMKvatpppsvlHLNKkagdlsnelVRHFLIECTPKGV 872
Cdd:cd09944      4 SQPWFHGGISRDEAARLIRQQGlvDGVFLVRESQSNPGAFVLSLK---------HGQK---------IKHYQIIPIEDEG 65

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gi 1958676751  873 RL-----KGCSNepyFGSLTALVCQHSITPLALPCKL 904
Cdd:cd09944     66 QWyftldDGVTK---FYDLLQLVEFYQLNAGSLPTRL 99

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.

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gi 1958676751  798 WYKADISREQAIAML--KDKAPGSFIVRDSHSFRGAYGLAM 836
Cdd:cd10347      3 WYHGKISREVAEALLlrEGGRDGLFLVRESTSAPGDYVLSL 43

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. 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 1958676751  798 WYKADISREQAIAMLKDKA-PGSFIVRDSHSFRGAYGLAMKVA 839
Cdd:cd09943      3 WYYGRITRHQAETLLNEHGhEGDFLIRDSESNPGDYSVSLKAP 45

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target 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.

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gi 1958676751  798 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGL 834
Cdd:cd09926      9 WYFGPMSRQEAQELLQGQRHGVFLVRDSSTIPGDYVL 45

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.

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gi 1958676751  795 SKFWYKADISREQAIAMLKdKAP--GSFIVRDSHSFRGAYGLAMKV 838
Cdd:cd09932      3 SKEWFHANLTREQAEEMLM-RVPrdGAFLVRPSETDPNSFAISFRA 47