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 568970343  790 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 869
Cdd:cd09927     1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 568970343  870 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 906
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 568970343  790 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 869
Cdd:cd09927     1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 568970343  870 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 906
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 568970343    929 QGAACNVWYLNSVEMESLTGHQAVQKALSMTLVQEPPPVSTV--VHFKVSAQGITLTDNQRKlFFRRHYPVSSVIFCALD 1006
Cdd:smart00462    2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPqkVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVG 80

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|.
gi 568970343   1007 PQDrkwikdgpsSKVFGFVARKQGSaTDNVCHLF--AEHDPEQPASAIVNF 1055
Cdd:smart00462   81 PDD---------LDVFGYIARDPGS-SRFACHVFrcEKAAEDIALAIGQAF 121

SH2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568970343   794 WYKADISREQAIAMLK-DKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkagdlsNELVRHFLIECTPKGVRLkg 872
Cdd:pfam00017    1 WYHGKISRQEAERLLLnGKPDGTFLVRESESTPGGYTL---------SVRD---------DGKVKHYKIQSTDNGGYY-- 60

                           90
                   ....*....|....
gi 568970343   873 CSNEPYFGSLTALV 886
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 568970343  790 TSKFWYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVATPPPSVLHLNKKaGDLSNELVRHFLIECTPKGVR 869
Cdd:cd09927     1 TSKYWYKPNISRDQAIALLKDKPPGTFLVRDSTTYKGAYGLAVKVATPPPGVNPFEAK-GDPESELVRHFLIEPSPKGVK 79

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 568970343  870 LKGCSNEPYFGSLTALVCQHSITPLALPCKLLIPERD 906
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 568970343    929 QGAACNVWYLNSVEMESLTGHQAVQKALSMTLVQEPPPVSTV--VHFKVSAQGITLTDNQRKlFFRRHYPVSSVIFCALD 1006
Cdd:smart00462    2 SGVSFRVKYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPqkVILSISSRGVKLIDEDTK-AVLHEHPLRRISFCAVG 80

                            90       100       110       120       130
                    ....*....|....*....|....*....|....*....|....*....|.
gi 568970343   1007 PQDrkwikdgpsSKVFGFVARKQGSaTDNVCHLF--AEHDPEQPASAIVNF 1055
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 568970343    794 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRlkGC 873
Cdd:smart00252    3 WYHGFISREEAEKLLKNEGDGDFLVRDSESSPGDYVLSVRV------------------KGKVKHYRIRRNEDGKF--YL 62

                            90       100
                    ....*....|....*....|.
gi 568970343    874 SNEPYFGSLTALVCQHSITPL 894
Cdd:smart00252   63 EGGRKFPSLVELVEHYQKNSL 83

SH2 domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568970343   794 WYKADISREQAIAMLK-DKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkagdlsNELVRHFLIECTPKGVRLkg 872
Cdd:pfam00017    1 WYHGKISRQEAERLLLnGKPDGTFLVRESESTPGGYTL---------SVRD---------DGKVKHYKIQSTDNGGYY-- 60

                           90
                   ....*....|....
gi 568970343   873 CSNEPYFGSLTALV 886
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 568970343  794 WYKADISREQAIAMLKDKAPGSFIVRDShSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRLKgc 873
Cdd:cd09930     8 WLVGDINRTQAEELLRGKPDGTFLIRES-STQGCYACSVVC------------------NGEVKHCVIYKTETGYGFA-- 66

                          90       100
                  ....*....|....*....|....
gi 568970343  874 snEPY--FGSLTALVCQHSITPLA 895
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 568970343  794 WYKADISREQAIAML-KDKAPGSFIVRDSHSFRGAYGLAMKVatpppsvlhlnkkagdlsNELVRHFLIECTPKGVRLKG 872
Cdd:cd10354     2 WFHGKISREEAYNMLvKVGGPGSFLVRESDNTPGDYSLSFRV------------------NEGIKHFKIIPTGNNQFMMG 63

                          90
                  ....*....|....
gi 568970343  873 csnEPYFGSLTALV 886
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 568970343  794 WYKADISREQA--IAMLKDKAPGSFIVRDSHSFRGAYGLamkvatpppSVLHlnkkAGDLSNELVRHFLIECTPKG 867
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 568970343  794 WYKADISREQAIAMLKDKAP-GSFIVRDShSFRGAYGLA--MKVATPPpsvlhlnkkagdlsneLVRHFLIECTPKG--- 867
Cdd:cd09934     8 WYVGDMSRQRAESLLKQEDKeGCFVVRNS-STKGLYTVSlfTKVPGSP----------------HVKHYHIKQNARSefy 70

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 568970343  868 VRLKGCsnepyFGSLTALVCQHSITPLALPCKLLIP 903
Cdd:cd09934    71 LAEKHC-----FETIPELINYHQHNSGGLATRLKYP 101

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. 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 568970343  794 WYKADISREQAIAMLKDKA-PGSFIVRDSHSFRGAYGLamkvatpppSVLHLNKKagdlsnelVRHFLIECtpKGVRLKG 872
Cdd:cd09931     2 WFHGHLSGKEAEKLLLEKGkPGSFLVRESQSKPGDFVL---------SVRTDDDK--------VTHIMIRC--QGGKYDV 62

                          90       100
                  ....*....|....*....|..
gi 568970343  873 CSNEPyFGSLTALVCQHSITPL 894
Cdd:cd09931    63 GGGEE-FDSLTDLVEHYKKNPM 83

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 568970343  794 WYKADISREQAIAML----KDkapGSFIVRDSHSFRGAYGL 830
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 568970343  794 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMKvatpppsvlhlnkkagdlSNELVRHFLIECTPKGVRLkgC 873
Cdd:cd09935     5 WYHGPISRNAAEYLLSSGINGSFLVRESESSPGQYSISLR------------------YDGRVYHYRISEDSDGKVY--V 64

                          90       100       110
                  ....*....|....*....|....*....|
gi 568970343  874 SNEPYFGSLTALVCQHSITPLALPCKLLIP 903
Cdd:cd09935    65 TQEHRFNTLAELVHHHSKNADGLITTLRYP 94

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins are a family of phorbol ester- and diacylglycerol-responsive GTPase-activating proteins. Alpha1-chimerin (formerly known as n-chimerin) and alpha2-chimerin are alternatively spliced products of a single gene, as are beta1- and beta2-chimerin. alpha1- and beta1-chimerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas alpha2- and beta2-chimerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors. All of the isoforms contain a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. Other C1 domain-containing diacylglycerol receptors including: PKC, Munc-13 proteins, phorbol ester binding scaffolding proteins involved in Ca2+-stimulated exocytosis, and RasGRPs, diacylglycerol-activated guanine-nucleotide exchange factors (GEFs) for Ras and Rap1. 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 568970343  795 YKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGLAMK 833
Cdd:cd10352     9 YHGLISREEAEQLLSGASDGSYLIRESSRDDGYYTLSLR 47

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 568970343  794 WYKADISREQAIAML--KDKAPGSFIVRDSHSFRGAYGLAM 832
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 568970343  794 WYKADISREQAIAMLKDKA-PGSFIVRDSHSFRGAYGLAMKVA 835
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 568970343  794 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGAYGL 830
Cdd:cd09926     9 WYFGPMSRQEAQELLQGQRHGVFLVRDSSTIPGDYVL 45

Src homology 2 domain found in hematopoietic SH2 (HSH2) protein; HSH2 is thought to function as an adapter protein involved in tyrosine kinase signaling. It may also be involved in regulating cytokine signaling and cytoskeletal reorganization in hematopoietic cells. HSH2 contains several putative protein-binding motifs, SH3-binding proline-rich regions, and phosphotyrosine sites, but lacks enzymatic motifs. HSH2 was found to interact with cytokine-regulated tyrosine kinase c-FES and an activated Cdc42-associated tyrosine kinase ACK1. HSH2 binds c-FES through both its C-terminal region and its N-terminal region including the SH2 domain and binds ACK1 via its N-terminal proline-rich region. Both kinases bound and tyrosine-phosphorylated HSH2 in mammalian 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.

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gi 568970343  794 WYKADISREQAIAMLKDKAPGSFIVRDSHSFRGaYGLAMKVATPppsvlhlnkkagdlsnelVRHFLIECTPKGVRLKGC 873
Cdd:cd09946     9 WFHGAISREAAENMLESQPLGSFLIRVSHSHVG-YTLSYKAQSS------------------CRHFMVKLLDDGTFMIPG 69

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gi 568970343  874 SNEPYfGSLTALVCQHSITPL 894
Cdd:cd09946    70 EKVAH-TSLHALVTFHQQKPI 89

JNK-interacting protein-like (JIP) Phosphotyrosine-binding (PTB) domain; JIP is a mitogen-activated protein kinase scaffold protein. JIP consists of a C-terminal SH3 domain, followed by a PTB domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Dab-like subgroup.

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gi 568970343  933 CNVWYLNSVEMESLTGH----QAVQKALS---MTLVQEPPpvsTVVHFKVSAQGITLTDNQRKLFFRR----HY--PVSS 999
Cdd:cd01212     5 FLLGFLGSVEVPYHKGNdvlcQAMQKIATarrLTVHLRPP---QSCILEISDRGLKMVDRSKPNKKDGkpciHYfySLKN 81

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gi 568970343 1000 VIFCALDPQDrkwikdgpsSKVFGFV 1025
Cdd:cd01212    82 ISFCGFHPRN---------SRYFGFI 98