MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474   32 REEQIRRWKEREAAMERKESLPVK----SRPKKENGKSVHWKLGADKQVWVWVMGEHHLDKPYDVLCDEILAEREHLRAA 107
Cdd:PTZ00121 1207 KAEEERKAEEARKAEDAKKAEAVKkaeeAKKDAEEAKKAEEERNNEEIRKFEEARMAHFARRQAAIKAEEARKADELKKA 1286

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474  108 ----KDSELRKTQSLELANSLKIKSQNCDLQAMKKTEPQNVTRKA------------ASEEASGQGPRAIPTRKDDKAQT 171
Cdd:PTZ00121 1287 eekkKADEAKKAEEKKKADEAKKKAEEAKKADEAKKKAEEAKKKAdaakkkaeeakkAAEAAKAEAEAAADEAEAAEEKA 1366

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 206597474  172 KPVKEKDHEEMKQTEDEKTKQIYKSWKEDSEWQASLRKSKAADEKRRSLAKQAREDYKRLSQRGRSGDGLQ 242
Cdd:PTZ00121 1367 EAAEKKKEEAKKKADAAKKKAEEKKKADEAKKKAEEDKKKADELKKAAAAKKKADEAKKKAEEKKKADEAK 1437

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 206597474   314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLI-DASANSYSFlgVDQLQHATLADLVEYHK 391
Cdd:smart00252   2 PWYHGFISREEAEKLLKNEGDGDFLVRDSESSPGdYVLSVRVKGKVKHYRIrRNEDGKFYL--EGGRKFPSLVELVEHYQ 79

                   ....
gi 206597474   392 EEPI 395
Cdd:smart00252  80 KNSL 83

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474   32 REEQIRRWKEREAAMERKESLPVK----SRPKKENGKSVHWKLGADKQVWVWVMGEHHLDKPYDVLCDEILAEREHLRAA 107
Cdd:PTZ00121 1207 KAEEERKAEEARKAEDAKKAEAVKkaeeAKKDAEEAKKAEEERNNEEIRKFEEARMAHFARRQAAIKAEEARKADELKKA 1286

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474  108 ----KDSELRKTQSLELANSLKIKSQNCDLQAMKKTEPQNVTRKA------------ASEEASGQGPRAIPTRKDDKAQT 171
Cdd:PTZ00121 1287 eekkKADEAKKAEEKKKADEAKKKAEEAKKADEAKKKAEEAKKKAdaakkkaeeakkAAEAAKAEAEAAADEAEAAEEKA 1366

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 206597474  172 KPVKEKDHEEMKQTEDEKTKQIYKSWKEDSEWQASLRKSKAADEKRRSLAKQAREDYKRLSQRGRSGDGLQ 242
Cdd:PTZ00121 1367 EAAEKKKEEAKKKADAAKKKAEEKKKADEAKKKAEEDKKKADELKKAAAAKKKADEAKKKAEEKKKADEAK 1437

Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains a single 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 206597474 307 KNSDTIAPWFHGILTLKKANELLSTGVPGSFLIRVSEKIKGYALSYLSEEGCKHFLIDASANSYSFLGVDQLQHATLADL 386
Cdd:cd10351    1 RNTKTIAPWFHGIISREEAEALLMNATEGSFLVRVSEKIWGYTLSYRLQSGFKHFLVDASGDFYSFLGVDPNRHATLTDL 80

                         90       100
                 ....*....|....*....|...
gi 206597474 387 VEYHKEEPITSLGKELLLYPCGQ 409
Cdd:cd10351   81 IDFHKEEIITTSGGELLQEPCGQ 103

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 206597474 314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEG-CKHFLIDASANSYSFLGVDQLQHATLADLVEYH 390
Cdd:cd00173    1 PWFHGSISREEAERLLRGKPDGTFLVRESSSEPGdYVLSVRSGDGkVKHYLIERNEGGYYLLGGSGRTFPSLPELVEHY 79

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); SH2D2A and SH7 both contain a single 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 206597474 314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKGYALSYLSEEGCKHFLIDASANSYSFLGVDQLQHATLADLVEYH 390
Cdd:cd10349    1 AWFHGFITRREAERLLEPKPQGCYLVRFSESAVTFVLSYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARLQDLLLHY 77

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 206597474  315 WFHGILTLKKANELL-STGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGvDQLQHATLADLVEYH 390
Cdd:pfam00017   1 WYHGKISRQEAERLLlNGKPDGTFLVRESESTPGgYTLSVRDDGKVKHYKIQSTDNGGYYIS-GGVKFSSLAELVEHY 77

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 206597474 315 WFHGILTLKKANELL-STGVPGSFLIRVSEKIKG-YALSYLSEEG-CKHFLIDASANSYSFLGVDQLQhaTLADLVEYHK 391
Cdd:cd09931    2 WFHGHLSGKEAEKLLlEKGKPGSFLVRESQSKPGdFVLSVRTDDDkVTHIMIRCQGGKYDVGGGEEFD--SLTDLVEHYK 79

                 ....
gi 206597474 392 EEPI 395
Cdd:cd09931   80 KNPM 83

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related (Fes/Fps/Fer) proteins; The Fps family consists of members Fps/Fes and Fer/Flk/Tyk3. They are cytoplasmic protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. Fes/Fps/Fer contains three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. Members here include: Fps/Fes, Fer, Kin-31, and 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 206597474 314 PWFHGILTLKKANELLSTgvPGSFLIRVSEKIKG----YALSYLSEEGCKHFLIDASANSYsfLGVDQLQHATLADLVEY 389
Cdd:cd10361    7 PYYHGLLPREDAEELLKN--DGDFLVRKTEPKGGgkrkLVLSVRWDGKIRHFVINRDDGGK--YYIEGKSFKSISELINY 82

                 ....*...
gi 206597474 390 HKE--EPI 395
Cdd:cd10361   83 YQKtkEPI 90

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 206597474 314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGVDQlQHATLADLVEYHKE 392
Cdd:cd09935    4 SWYHGPISRNAAEYLLSSGINGSFLVRESESSPGqYSISLRYDGRVYHYRISEDSDGKVYVTQEH-RFNTLAELVHHHSK 82

                         90
                 ....*....|....*..
gi 206597474 393 EP---ITslgkeLLLYP 406
Cdd:cd09935   83 NAdglIT-----TLRYP 94

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 206597474 315 WFHGILTLKKANELLST-GVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGVDQLqhATLADLVEYHKE 392
Cdd:cd10340    2 WFHPVISGIEAENLLKTrGVDGSFLARPSKSNPGdFTLSVRRGDEVTHIKIQNTGDYYDLYGGEKF--ATLSELVQYYME 79

                 ..
gi 206597474 393 EP 394
Cdd:cd10340   80 QH 81

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 206597474 312 IAP----WFHGILTLKKANE-LLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGvdqLQHATLAD 385
Cdd:cd10353   14 TAPptnqWYHGRLDRTIAEErLRQAGKLGSYLIRESDRRPGsFVLSFLSRTGVNHFRIIAMCGDYYIGG---RRFSSLSD 90

                 ....*
gi 206597474 386 LVEYH 390
Cdd:cd10353   91 LIGYY 95

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 206597474 314 PWFHGILTLKKANELLSTgVP--GSFLIRVSEK-IKGYALSYLSEEGCKHFLIDASANSYsflGVDQLQHATLADLVEYH 390
Cdd:cd09932    5 EWFHANLTREQAEEMLMR-VPrdGAFLVRPSETdPNSFAISFRAEGKIKHCRIKQEGRLF---VIGTSQFESLVELVSYY 80

                 ....
gi 206597474 391 KEEP 394
Cdd:cd09932   81 EKHP 84

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the N-terminus SH2 domains of both Syk and Zap70. 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 206597474 314 PWFHGILTLKKANELLSTG--VPGSFLIRVS-EKIKGYALSYLSEEGCKHFLIDASAN-SYSFLGvdQLQHATLADLVEY 389
Cdd:cd09938    2 PFFYGSITREEAEEYLKLAgmSDGLFLLRQSlRSLGGYVLSVCHGRKFHHYTIERQLNgTYAIAG--GKAHCGPAELCEY 79

                         90       100
                 ....*....|....*....|.
gi 206597474 390 HKEEP---ITslgkeLLLYPC 407
Cdd:cd09938   80 HSTDLdglVC-----LLRKPC 95

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 314 PWFHGILTLKK--ANELLS---TGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDAS--ANSYSFLGVDQLQHATLAD 385
Cdd:cd10341    5 PWFHGKLGDGRdeAEKLLLeycEGGDGTFLVRESETFVGdYTLSFWRNGKVQHCRIRSRqeNGEKKYYLTDNLVFDSLYE 84

                         90
                 ....*....|..
gi 206597474 386 LVEYHKEEPITS 397
Cdd:cd10341   85 LIDYYRQNPLRC 96

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. 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 206597474 314 PWFHGILTLKKANELLSTGVP---GSFLIRVSEKIKG-YALSYLSEEGCKHFLIdaSANSYSFLGVDQLQHATLADLVEY 389
Cdd:cd10411    9 PWFHGTLSRVKAAQLVLAGGPrshGLFVIRQSETRPGeYVLTFNFQGKAKHLRL--SLNGHGQCHVQHLWFQSVFDMLRH 86

                 ....*.
gi 206597474 390 HKEEPI 395
Cdd:cd10411   87 FHTHPI 92

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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 314 PWFHGILTLKKANELLSTGvpGSFLIRVSEKIKG-YALSYLSEEGCKHF-LIDASANsysflgVDQLQHA--TLADLVEY 389
Cdd:cd09925    8 PWYHGKMSRRDAESLLQTD--GDFLVRESTTTPGqYVLTGMQNGQPKHLlLVDPEGV------VRTKDRVfeSISHLINY 79

                         90
                 ....*....|....*..
gi 206597474 390 HKEE--PITSLGKELLL 404
Cdd:cd09925   80 HVTNglPIISEGSELHL 96

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSysfLGVDQLQH-ATLADLVEYHK 391
Cdd:cd09937    4 PWFHGKISREEAERLLQPPEDGLFLVRESTNYPGdYTLCVSFEGKVEHYRVIYRNGK---LTIDEEEYfENLIQLVEHYT 80

                 ..
gi 206597474 392 EE 393
Cdd:cd09937   81 KD 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 206597474 315 WFHGILTLKKANELLST-GVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSflgVDQLQHATLADLVEYHKE 392
Cdd:cd10409    3 WYYGNVTRHQAECALNErGVEGDFLIRDSESSPSdFSVSLKAVGKNKHFKVQLVDNVYC---IGQRRFNSMDELVEHYKK 79

                 ...
gi 206597474 393 EPI 395
Cdd:cd10409   80 API 82

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

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 206597474 314 PWFHGILTLKKANELLST--GVPGSFLIRVSE-KIKGYALSYLSEEGCKHFLI 363
Cdd:cd09944    6 PWFHGGISRDEAARLIRQqgLVDGVFLVRESQsNPGAFVLSLKHGQKIKHYQI 58

Src homology 2 domain found in SH2 domain-containing adapter protein E (SHE); SHE is expressed in heart, lung, brain, and skeletal muscle. 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. 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 206597474 314 PWFHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGVDQLQHATLADLVEYHKE 392
Cdd:cd10391    2 PWYHGSISRAEAESRLQPCKEASYLVRNSESGNSkYSIALKTSQGCVHIIVAQTKDNKYTLNQTSAVFDSIPEVVHYYSN 81

                         90
                 ....*....|....*.
gi 206597474 393 EPITSLGKE--LLLYP 406
Cdd:cd10391   82 EKLPFKGAEhmTLLHP 97

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated 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 206597474 314 PWFHGILTLKKANELLSTGVP---GSFLIRVSEKIKG-YALSYLSEEGCKHFLIdaSANSYSFLGVDQLQHATLADLVEY 389
Cdd:cd10412    9 PWFHGPISRVKAAQLVQLQGPdahGVFLVRQSETRRGeYVLTFNFQGRAKHLRL--SLTERGQCRVQHLHFPSVVDMLHH 86

                 ....*.
gi 206597474 390 HKEEPI 395
Cdd:cd10412   87 FQRSPI 92

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 314 PWFHGILTLKKA-NELLSTGVP-GSFLIRVSEKIKG-YALSYLSEE-----GCKHFLIDASANSYSFLgVDQLQHATLAD 385
Cdd:cd09933    4 EWFFGKIKRKDAeKLLLAPGNPrGTFLIRESETTPGaYSLSVRDGDdargdTVKHYRIRKLDNGGYYI-TTRATFPTLQE 82

                 ....*...
gi 206597474 386 LVEYHKEE 393
Cdd:cd09933   83 LVQHYSKD 90

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 206597474 316 FHGILTLKKANELLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHF-LIDASANSYSFLGvdQLQHATLADLV 387
Cdd:cd10352    9 YHGLISREEAEQLLSGASDGSYLIRESSRDDGyYTLSLRFNGKVKNYkLYYDGKNHYHYVG--EKRFDTIHDLV 80

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 315 WFHGILTLKKAN-ELLSTGVP-GSFLIRVSEKIKG-YALSY-----LSEEGCKHFLIDASANSYSFLgVDQLQHATLADL 386
Cdd:cd10368    5 WYFGKLGRKDAErQLLSFGNPrGTFLIRESETTKGaYSLSIrdwddMKGDHVKHYKIRKLDNGGYYI-TTRAQFETLQQL 83

                 ....*.
gi 206597474 387 VEYHKE 392
Cdd:cd10368   84 VQHYSE 89

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474 314 PWFHGILTLKKANE--LLSTGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGVDQLQHaTLADLVEYH 390
Cdd:cd10369    4 PWFFGAIKRADAEKqlLYSENQTGAFLIRESESQKGeFSLSVLDGGVVKHYRIRRLDEGGFFLTRRKTFS-TLNEFVNYY 82

Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast tumor kinase (Brk); Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumors. PTK6 (9). PTK6 contains a SH3 domain, a SH2 domain, and catalytic domains. For the case of the non-receptor protein-tyrosine kinases, the SH2 domain is typically involved in negative regulation of kinase activity by binding to a phosphorylated tyrosine residue near to the C terminus. The C-terminal sequence of PTK6 (PTSpYENPT where pY is phosphotyrosine) is thought to be a self-ligand for the SH2 domain. The structure of the SH2 domain resembles other SH2 domains except for a centrally located four-stranded antiparallel beta-sheet (strands betaA, betaB, betaC, and betaD). There are also differences in the loop length which might be responsible for PTK6 ligand specificity. There are two possible means of regulation of PTK6: autoinhibitory with the phosphorylation of Tyr playing a role in its negative regulation and autophosphorylation at this site, though it has been shown that PTK6 might phosphorylate signal transduction-associated proteins Sam68 and signal transducing adaptor family member 2 (STAP/BKS) in vivo. 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 206597474 314 PWFHGILTLKKANELLST--GVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLIDASANSYSFLGvDQLQHATLADLVEYH 390
Cdd:cd10358    3 PWFFGCISRSEAVRRLQAegNATGAFLIRVSEKPSAdYVLSVRDTQAVRHYKIWRRAGGRLHLN-EAVSFLSLPELVNYH 81

                         90
                 ....*....|....*..
gi 206597474 391 KEEPItSLGKELLLyPC 407
Cdd:cd10358   82 RAQSL-SHGLRLAA-PC 96

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. 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 206597474 313 APWFHGILTLKKANELLstGVPGSFLIRVSEKIKG-YALSYLSEEGCKHFLI------DASANSYSFLGVDQLQHATLAD 385
Cdd:cd10337    6 HAWYHGRIPRQVAESLV--QREGDFLVRDSLSSPGdYVLTCRWKGQPLHFKInrvvlrPSEAYTRVQYQFEDEQFDSIPA 83

                         90       100       110
                 ....*....|....*....|....*....|...
gi 206597474 386 LVEYH--KEEPITSLGKELLLYPCGQQDKLPDY 416
Cdd:cd10337   84 LVHFYvgNRRPISQASGAIISRPVNRTVPLRCL 116

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 206597474 308 NSDTIAPWFHGILTLKKANELLST-GVPGSFLIRVSEKIKGYALSYLSEEG------CKHFLIDASANSYSFLGVDQLqH 380
Cdd:cd10397    1 DSLEMYEWYSKNMTRSQAEQLLKQeGKEGGFIVRDSSKAGKYTVSVFAKSAgdpqgvIRHYVVCSTPQSQYYLAEKHL-F 79

                         90
                 ....*....|.
gi 206597474 381 ATLADLVEYHK 391
Cdd:cd10397   80 STIPELINYHQ 90

MAEBL; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474   95 DEILAEREHLRAAKDSELRKTQSLELANSLKIKSQncdlQAMKKTEPQNVTRKAASEEASGQGPRAIPTRKDDKAQTKPV 174
Cdd:PTZ00121 1305 DEAKKKAEEAKKADEAKKKAEEAKKKADAAKKKAE----EAKKAAEAAKAEAEAAADEAEAAEEKAEAAEKKKEEAKKKA 1380

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 206597474  175 KE--KDHEEMKQTEDEKTKQIYKSWKEDSEWQASLRKSKAADEKRRSLAKQAREDYKRLSQRGRSGDGLQ 242
Cdd:PTZ00121 1381 DAakKKAEEKKKADEAKKKAEEDKKKADELKKAAAAKKKADEAKKKAEEKKKADEAKKKAEEAKKADEAK 1450