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 5031855  411 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 489
Cdd:cd09929   1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 5031855  490 RGKEDFLSVSDIIDYFRKMPLLLIDGKNRGSRYQCTLtHAAG 531
Cdd:cd09929  81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 121

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    130 SPNEEEEAPVEDDADYEPPPSNDEEALQNSILPAKPFPNSNSMYIDRPPSGKTPQQPPVPPQRPMAALPPPPAGRNHSPL 209
Cdd:PHA03247 2632 SPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRLGRAAQASSPPQRPRRRAARPTVGSLTSLADPPPPPPTPEPA 2711

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    210 PPPQTNHEEPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAGRSLGEHlPKIQKPPLPP 289
Cdd:PHA03247 2712 PHALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPP-RRLTRPAVAS 2790

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    290 TTERHErSSPLPGKKPPVPKHGWGPDRRENDEddvhQRPLPqpaLLPMSSNTFPSRSTKPSPmnPLPSSHMPGAFSESNS 369
Cdd:PHA03247 2791 LSESRE-SLPSPWDPADPPAAVLAPAAALPPA----ASPAG---PLPPPTSAQPTAPPPPPG--PPPPSLPLGGSVAPGG 2860

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 5031855    370 SF-----PQSASLPPYFSQGPS----NRPPIRAEGRNFPLPLPNKPRPPSPAEEENSLNEE 421
Cdd:PHA03247 2861 DVrrrppSRSPAAKPAAPARPPvrrlARPAVSRSTESFALPPDQPERPPQPQAPPPPQPQP 2921

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 5031855  411 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 489
Cdd:cd09929   1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 5031855  490 RGKEDFLSVSDIIDYFRKMPLLLIDGKNRGSRYQCTLtHAAG 531
Cdd:cd09929  81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 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 5031855     420 EEWYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrGKEDFLSVS 499
Cdd:smart00252   1 QPWYHGFISREEAEKLLKN-EGDGDFLVRDSE--SSPGDYVLSVRVKGKVKHYRIRRNEDGKFYLE-----GGRKFPSLV 72

                           90
                   ....*....|.
gi 5031855     500 DIIDYFRKMPL 510
Cdd:smart00252  73 ELVEHYQKNSL 83

SAM domain (Sterile alpha motif);

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 5031855     12 VLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFL-NLTENDIQKFPKLRVPILSKLSQEINKNE 76
Cdd:pfam07647   1 VESWSLESVADWLRSIGLEQYTDNFRDQGITGAELLlRLTLEDLKRLGITSVGHRRKILKKIQELK 66

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    130 SPNEEEEAPVEDDADYEPPPSNDEEALQNSILPAKPFPNSNSMYIDRPPSGKTPQQPPVPPQRPMAALPPPPAGRNHSPL 209
Cdd:PHA03247 2632 SPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRLGRAAQASSPPQRPRRRAARPTVGSLTSLADPPPPPPTPEPA 2711

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    210 PPPQTNHEEPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAGRSLGEHlPKIQKPPLPP 289
Cdd:PHA03247 2712 PHALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPP-RRLTRPAVAS 2790

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    290 TTERHErSSPLPGKKPPVPKHGWGPDRRENDEddvhQRPLPqpaLLPMSSNTFPSRSTKPSPmnPLPSSHMPGAFSESNS 369
Cdd:PHA03247 2791 LSESRE-SLPSPWDPADPPAAVLAPAAALPPA----ASPAG---PLPPPTSAQPTAPPPPPG--PPPPSLPLGGSVAPGG 2860

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 5031855    370 SF-----PQSASLPPYFSQGPS----NRPPIRAEGRNFPLPLPNKPRPPSPAEEENSLNEE 421
Cdd:PHA03247 2861 DVrrrppSRSPAAKPAAPARPPvrrlARPAVSRSTESFALPPDQPERPPQPQAPPPPQPQP 2921

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 5031855  411 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 489
Cdd:cd09929   1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 5031855  490 RGKEDFLSVSDIIDYFRKMPLLLIDGKNRGSRYQCTLtHAAG 531
Cdd:cd09929  81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 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 5031855     420 EEWYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrGKEDFLSVS 499
Cdd:smart00252   1 QPWYHGFISREEAEKLLKN-EGDGDFLVRDSE--SSPGDYVLSVRVKGKVKHYRIRRNEDGKFYLE-----GGRKFPSLV 72

                           90
                   ....*....|.
gi 5031855     500 DIIDYFRKMPL 510
Cdd:smart00252  73 ELVEHYQKNSL 83

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 5031855  421 EWYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTTTNPYVLMVLYK-DKVYNIQIRYQKESQVYLLGTGLRgkedFLSVS 499
Cdd:cd00173   1 PWFHGSISREEAERLLRG-KPDGTFLVRESS--SEPGDYVLSVRSGdGKVKHYLIERNEGGYYLLGGSGRT----FPSLP 73

                ....*.
gi 5031855  500 DIIDYF 505
Cdd:cd00173  74 ELVEHY 79

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 5031855  418 LNEEWYVSYITRPEAEAALRKINQDGTFLVRDSSkkTTTNPYVLMVLYKDKVYNIQIryQKESQVYLLGTglrgkEDFLS 497
Cdd:cd09932   2 ESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSE--TDPNSFAISFRAEGKIKHCRI--KQEGRLFVIGT-----SQFES 72

                        90
                ....*....|...
gi 5031855  498 VSDIIDYFRKMPL 510
Cdd:cd09932  73 LVELVSYYEKHPL 85

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 5031855  421 EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTtnpYVLMVLYK----DKVYNIQIRYQKESQVYllgtgLRGKEDFL 496
Cdd:cd09934   7 EWYVGDMSRQRAESLLKQEDKEGCFVVRNSSTKGL---YTVSLFTKvpgsPHVKHYHIKQNARSEFY-----LAEKHCFE 78

                        90
                ....*....|
gi 5031855  497 SVSDIIDYFR 506
Cdd:cd09934  79 TIPELINYHQ 88

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        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  422 WYVSYITRPEAEAALRKINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIryqkesqvyllgtgLRGKEDFLSVSDI 501
Cdd:cd10343   5 WYHGNITRSKAEELLSKAGKDGSFLVRDS--ESVSGAYALCVLYQNCVHTYRI--------------LPNAEDKLSVQAS 68

                        90
                ....*....|....*
gi 5031855  502 ----IDYFRKMPLLL 512
Cdd:cd10343  69 egvpVRFFTTLPELI 83

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  420 EEWYVSYITRPEAEAALRKINQDGTFLVRDSSkkttTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTglrgkEDFLSVS 499
Cdd:cd09943   1 QPWYYGRITRHQAETLLNEHGHEGDFLIRDSE----SNPGDYSVSLKAPGRNKHFKVQVVDNVYCIGQ-----RKFHTMD 71

                        90
                ....*....|.
gi 5031855  500 DIIDYFRKMPL 510
Cdd:cd09943  72 ELVEHYKKAPI 82

Src homology 2 (SH2) domain found in Nck; 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  420 EEWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTNPYVLMVLYKDKVYNIQIryqkESQVYLLgtglrGKEDFLSVS 499
Cdd:cd10409   1 KEWYYGNVTRHQAECALNERGVEGDFLIRDSESSPSDFSVSLKAVGKNKHFKVQL----VDNVYCI-----GQRRFNSMD 71

                        90
                ....*....|..
gi 5031855  500 DIIDYFRKMPLL 511
Cdd:cd10409  72 ELVEHYKKAPIF 83

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  422 WYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTnpYVLMVLYKDKVYNIQIRYQKESQVYllgtglrGKEDFLSVSDI 501
Cdd:cd10355   8 WYHGNLTRHAAEALLLSNGVDGSYLLRNSNEGTGL--FSLSVRAKDSVKHFHVEYTGYSFKF-------GFNEFSSLQDF 78

                        90
                ....*....|
gi 5031855  502 IDYFRKMPLL 511
Cdd:cd10355  79 VKHFANQPLI 88

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  421 EWYVSYITRPEAEAALRKINQDGTFLVRDSSKkttTNPYVLMVLYKD--------KVYNIQIRYQkeSQVYllgtgLRGK 492
Cdd:cd10397   7 EWYSKNMTRSQAEQLLKQEGKEGGFIVRDSSK---AGKYTVSVFAKSagdpqgviRHYVVCSTPQ--SQYY-----LAEK 76

                        90
                ....*....|..
gi 5031855  493 EDFLSVSDIIDY 504
Cdd:cd10397  77 HLFSTIPELINY 88

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 5031855      12 VLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFLNLT-ENDIQKFPKLRVPILSKLSQEINK 74
Cdd:smart00454   1 VSQWSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTsEEDLKELGITKLGHRKKILKAIQK 64

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    130 SPNEEEEAPVEDDADYEPPPSNDEEALQNSILPAKPFPNSNSMYIDRPPSGKTPQQPPVPPQRPMAALPPPPAGRNHSPL 209
Cdd:PHA03247 2632 SPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRLGRAAQASSPPQRPRRRAARPTVGSLTSLADPPPPPPTPEPA 2711

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    210 PPPQTNHEEPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAGRSLGEHlPKIQKPPLPP 289
Cdd:PHA03247 2712 PHALVSATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPP-RRLTRPAVAS 2790

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    290 TTERHErSSPLPGKKPPVPKHGWGPDRRENDEddvhQRPLPqpaLLPMSSNTFPSRSTKPSPmnPLPSSHMPGAFSESNS 369
Cdd:PHA03247 2791 LSESRE-SLPSPWDPADPPAAVLAPAAALPPA----ASPAG---PLPPPTSAQPTAPPPPPG--PPPPSLPLGGSVAPGG 2860

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 5031855    370 SF-----PQSASLPPYFSQGPS----NRPPIRAEGRNFPLPLPNKPRPPSPAEEENSLNEE 421
Cdd:PHA03247 2861 DVrrrppSRSPAAKPAAPARPPvrrlARPAVSRSTESFALPPDQPERPPQPQAPPPPQPQP 2921

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which 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. 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 5031855  421 EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTtnpYVLMVLYKDK------VYNIQIRYQKESQVYLLGTGLrgked 494
Cdd:cd10398   7 EWYHKNITRNQAERLLRQESKEGAFIVRDSRHLGS---YTISVFTRARrsteasIKHYQIKKNDSGQWYVAERHL----- 78

                        90
                ....*....|
gi 5031855  495 FLSVSDIIDY 504
Cdd:cd10398  79 FQSIPELIQY 88

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 5031855  422 WYVSYITRPEAEAALRK-INqdGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYllgtgLRGKEDFLSVSD 500
Cdd:cd09935   5 WYHGPISRNAAEYLLSSgIN--GSFLVRES--ESSPGQYSISLRYDGRVYHYRISEDSDGKVY-----VTQEHRFNTLAE 75

                ....*....
gi 5031855  501 IIDYFRKMP 509
Cdd:cd09935  76 LVHHHSKNA 84

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide variety of pathways including regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. An adapter protein, SHC has been implicated in Ras activation following the stimulation of a number of different receptors, including growth factors [insulin, epidermal growth factor (EGF), nerve growth factor, and platelet derived growth factor (PDGF)], cytokines [interleukins 2, 3, and 5], erythropoietin, and granulocyte/macrophage colony-stimulating factor, and antigens [T-cell and B-cell receptors]. SHC has been shown to bind to tyrosine-phosphorylated receptors, and receptor stimulation leads to tyrosine phosphorylation of SHC. Upon phosphorylation, SHC interacts with another adapter protein, Grb2, which binds to the Ras GTP/GDP exchange factor mSOS which leads to Ras activation. SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation. 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 5031855  420 EEWYVSYITRPEAEAALRkinQDGTFLVRDSSkkTTTNPYVL 461
Cdd:cd09925   7 EPWYHGKMSRRDAESLLQ---TDGDFLVREST--TTPGQYVL 43

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar proteins; The adaptor proteins here include homologs Grb2 in humans, Sex muscle abnormal protein 5 (Sem-5) in Caenorhabditis elegans, and Downstream of receptor kinase (drk) in Drosophila melanogaster. They are composed of one SH2 and two SH3 domains. Grb2/Sem-5/drk regulates the Ras pathway by linking the tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state. The SH2 domain of Grb2/Sem-5/drk binds class II phosphotyrosyl peptides while its SH3 domain binds to Sos and Sos-derived, proline-rich peptides. Besides it function in Ras signaling, Grb2 is also thought to play a role in apoptosis. Unlike most SH2 structures in which the peptide binds in an extended conformation (such that the +3 peptide residue occupies a hydrophobic pocket in the protein, conferring a modest degree of selectivity), Grb2 forms several hydrogen bonds via main chain atoms with the side chain of +2 Asn. 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 5031855  422 WYVSYITRPEAEAALRKINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrgKEDFLSVSDI 501
Cdd:cd09941   5 WFHGKISRAEAEEILMNQRPDGAFLIRES--ESSPGDFSLSVKFGNDVQHFKVLRDGAGKYFLW------VVKFNSLNEL 76

                ....*.
gi 5031855  502 IDYFRK 507
Cdd:cd09941  77 VDYHRT 82

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 5031855  422 WYVSYITRPEAEAALRkINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIRYQKESQvYLLGtglRGKEDFLSVSDI 501
Cdd:cd10392   3 WYHGAISRTDAENLLR-LCKEASYLVRNS--ETSKNDFSLSLKSSQGFMHMKLSRTKEHK-YVLG---QNSPPFSSVPEI 75

                        90
                ....*....|.
gi 5031855  502 IDYF--RKMPL 510
Cdd:cd10392  76 IHHYasRKLPI 86

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    203 GRNHSPLPPPQTNHE-----EPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPS--------- 268
Cdd:PHA03247  250 GDIAAPAPPPVVGEGadrapETARGATGPPPPPEAAAPNGAAAPPDGVWGAALAGAPLALPAPPDPPPPAPagdaeeedd 329

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    269 --------IPAGR-----SLGehLPKIQKPP-LPPTT-------ERHERSSPLPGKKPPVPKHGWGPDRRENDEDDVHQR 327
Cdd:PHA03247  330 edgamevvSPLPRprqhyPLG--FPKRRRPTwTPPSSledlsagRHHPKRASLPTRKRRSARHAATPFARGPGGDDQTRP 407

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    328 PLPQPALLPMSSNTFPSRSTKPSPMNPLPSSHMPGafseSNSSFPQSASLPPYFSQGPSNRPPIRAEGRnfPLPLPNKPR 407
Cdd:PHA03247  408 AAPVPASVPTPAPTPVPASAPPPPATPLPSAEPGS----DDGPAPPPERQPPAPATEPAPDDPDDATRK--ALDALRERR 481

                  ....
gi 5031855    408 PPSP 411
Cdd:PHA03247  482 PPEP 485

N-terminal Src homology 2 (N-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): [IVL]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 5031855  422 WYVSYITRPEAEAALRKINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIryQKESQVYLLGTGlrgkEDFLSVSDI 501
Cdd:cd10340   2 WFHPVISGIEAENLLKTRGVDGSFLARPS--KSNPGDFTLSVRRGDEVTHIKI--QNTGDYYDLYGG----EKFATLSEL 73

                        90
                ....*....|.
gi 5031855  502 IDYFRKMPLLL 512
Cdd:cd10340  74 VQYYMEQHGQL 84

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

                        10        20        30
                ....*....|....*....|....*....|.
gi 5031855  421 EWYVSYITRPEAEAALrKINQDGTFLVRDSS 451
Cdd:cd09923   1 GWYWGGITRYEAEELL-AGKPEGTFLVRDSS 30

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 5031855  421 EWYVSYITRPEAEAALRKINQDGTFLVRDSSkkTTTNPYVLMVLYKDKVYNIQIRyQKESQVYLLGtGLRgkedFLSVSD 500
Cdd:cd10354   1 IWFHGKISREEAYNMLVKVGGPGSFLVRESD--NTPGDYSLSFRVNEGIKHFKII-PTGNNQFMMG-GRY----FSSLDD 72

                ....*
gi 5031855  501 IIDYF 505
Cdd:cd10354  73 VIDRY 77

SAM domain of Scm-like-3MBT3,4 proteins of Polycomb group; SAM (sterile alpha motif) domain of Scm-like-3MBT3,4 (Sex comb on midleg, Malignant brain tumor) subfamily proteins (also known as L3mbtl3,4 proteins) is a putative protein-protein interaction domain. Proteins of this subfamily are predicted transcriptional regulators belonging to Polycomb group. The majority of them are multidomain proteins: in addition to the C-terminal SAM domain, they contain three MBT repeats and Zn finger domain. Murine L3mbtl3 protein of this subfamily is essential for maturation of myeloid progenitor cells during differentiation. Human L3mbtl4 is a potential tumor suppressor gene in breast cancer, while deregulation of L3MBTL3 is associated with neuroblastoma.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 5031855   12 VLGWDPDSLADYFKKL-NYKDCEKAVKKYHIDGARFLNLTENDIQKFPKLRV 62
Cdd:cd09582   1 VLRWSVDEVAEFVQSLpGCEEHAKVFRDEQIDGEAFLLLTQSDLVKILGIKL 52

N-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 the 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 N-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 5031855  404 NKPRPPSPAEEENslneEWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTTTnpYVLMVLYKDKVYNIQIryqkesqVY 483
Cdd:cd10353   7 EEVAIPLTAPPTN----QWYHGRLDRTIAEERLRQAGKLGSYLIRESDRRPGS--FVLSFLSRTGVNHFRI-------IA 73

                        90       100
                ....*....|....*....|....*....
gi 5031855  484 LLGTGLRGKEDFLSVSDIIDYFRKMPLLL 512
Cdd:cd10353  74 MCGDYYIGGRRFSSLSDLIGYYSHVSCLL 102

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    163 AKPFPNSNSMYIDRPPSGKTPQQPPVPPQRPMAALPPPPAGRNH-----------SPLPPPQTNHEEPSRSRNHKTAKLP 231
Cdd:PHA03247 2591 APPQSARPRAPVDDRGDPRGPAPPSPLPPDTHAPDPPPPSPSPAanepdphppptVPPPERPRDDPAPGRVSRPRRARRL 2670

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    232 APSIDRSTKP--PLDRSLAPfDREPFTLGKKPPFSDKPSIPAGRslgehlPKIQKPPLPPTTERHERSSPLPGKKPPVPk 309
Cdd:PHA03247 2671 GRAAQASSPPqrPRRRAARP-TVGSLTSLADPPPPPPTPEPAPH------ALVSATPLPPGPAAARQASPALPAAPAPP- 2742

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855    310 hgwgpdrrendeddvhqrPLPQPALLPMSSNTFPSRSTKPSPMNPLPSShMPGAFSESNSSFPQSASLPPYFSQGPSNR- 388
Cdd:PHA03247 2743 ------------------AVPAGPATPGGPARPARPPTTAGPPAPAPPA-APAAGPPRRLTRPAVASLSESRESLPSPWd 2803

                         250       260
                  ....*....|....*....|....*.
gi 5031855    389 ---PPIRAEGRNFPLPLPNKPRPPSP 411
Cdd:PHA03247 2804 padPPAAVLAPAAALPPAASPAGPLP 2829

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in the hematopoietic cells, in neural tissues, liver, and adipose tissue. There are two alternatively spliced forms of Lyn. Lyn plays an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation, triggering a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phospholipase C2 (PLC2) and phosphatidyl inositol-3 kinase. These kinases play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FC RIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1 which further down modulate signaling pathways, attenuate cell activation and can mediate tolerance. Lyn also plays a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1) leading to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. It is the primary Src family member involved in signaling downstream of the B cell receptor. Lyn plays an unusual, 2-fold role in B cell receptor signaling; it is essential for initiation of signaling but is also later involved in negative regulation of the signal. Lyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5031855  420 EEWYVSYITRPEAEAA-LRKINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGLRGKEDFLSV 498
Cdd:cd10364   3 EEWFFKDITRKDAERQlLAPGNSAGAFLIRES--ETLKGSYSLSVRDYDPQHGDVIKHYKIRSLDNGGYYISPRITFPCI 80

                ....*....
gi 5031855  499 SDIIDYFRK 507
Cdd:cd10364  81 SDMIKHYQK 89

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. 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. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. 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 5031855  422 WYVSYITRPEAEAALRkINQDGTFLVRDSskKTTTNPYVLMVLYKDKVYNIQIRYQKESQvYLLGTGLRgkeDFLSVSDI 501
Cdd:cd09945   3 WYHGAITRIEAESLLR-PCKEGSYLVRNS--ESTKQDYSLSLKSAKGFMHMRIQRNETGQ-YILGQFSR---PFETIPEM 75

                        90
                ....*....|
gi 5031855  502 IDYF--RKMP 509
Cdd:cd09945  76 IRHYclNKLP 85