polyadenylate binding protein, human types 1, 2, 3, 4 family; These eukaryotic proteins recognize the poly-A of mRNA and consists of four tandem RNA recognition domains at the N-terminus (rrm: pfam00076) followed by a PABP-specific domain (pfam00658) at the C-terminus. The protein is involved in the transport of mRNA's from the nucleus to the cytoplasm. There are four paralogs in Homo sapiens which are expressed in testis, platelets, broadly expressed and of unknown tissue range.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 159 LAQLRDGRHVVLGEDSAHARLQDLLLHYtahpLSPYGETLTEPLARQtpePAGLS-LRTEESNFGSKSQDPNPQYSPIIK 237
Cdd:TIGR01628 360 LAQRKEQRRAHLQDQFMQLQPRMRQLPM----GSPMGGAMGQPPYYG---QGPQQqFNGQPLGWPRMSMMPTPMGPGGPL 432

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2217272136 238 QGQAPVPMQKEGAGEKEPSQLL--RPKPPIPAkpqlPPEVYTIPVPRHRPAPRPKPSN 293
Cdd:TIGR01628 433 RPNGLAPMNAVRAPSRNAQNAAqkPPMQPVMY----PPNYQSLPLSQDLPQPQSTASQ 486

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 2217272136  101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSES-AVTFVLTYRSRTCCRHFLLAQLRDGRhVVLGEDSAHARL 179
Cdd:smart00252   3 WYHGFISRE----------EAEKLLKNEGDGDFLVRDSESsPGDYVLSVRVKGKVKHYRIRRNEDGK-FYLEGGRKFPSL 71

                           90
                   ....*....|...
gi 2217272136  180 QDLLLHYTAHPLS 192
Cdd:smart00252  72 VELVEHYQKNSLG 84

polyadenylate binding protein, human types 1, 2, 3, 4 family; These eukaryotic proteins recognize the poly-A of mRNA and consists of four tandem RNA recognition domains at the N-terminus (rrm: pfam00076) followed by a PABP-specific domain (pfam00658) at the C-terminus. The protein is involved in the transport of mRNA's from the nucleus to the cytoplasm. There are four paralogs in Homo sapiens which are expressed in testis, platelets, broadly expressed and of unknown tissue range.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 159 LAQLRDGRHVVLGEDSAHARLQDLLLHYtahpLSPYGETLTEPLARQtpePAGLS-LRTEESNFGSKSQDPNPQYSPIIK 237
Cdd:TIGR01628 360 LAQRKEQRRAHLQDQFMQLQPRMRQLPM----GSPMGGAMGQPPYYG---QGPQQqFNGQPLGWPRMSMMPTPMGPGGPL 432

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2217272136 238 QGQAPVPMQKEGAGEKEPSQLL--RPKPPIPAkpqlPPEVYTIPVPRHRPAPRPKPSN 293
Cdd:TIGR01628 433 RPNGLAPMNAVRAPSRNAQNAAqkPPMQPVMY----PPNYQSLPLSQDLPQPQSTASQ 486

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 100 AWFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESAVTFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARL 179
Cdd:cd10349     1 AWFHGFITRR----------EAERLLEPKPQGCYLVRFSESAVTFVLSYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARL 70

                  ....*..
gi 2217272136 180 QDLLLHY 186
Cdd:cd10349    71 QDLLLHY 77

Src homology 2 domain found in hematopoietic SH2 (HSH2) protein; HSH2 is thought to function as an adapter protein involved in tyrosine kinase signaling. It may also be involved in regulating cytokine signaling and cytoskeletal reorganization in hematopoietic cells. HSH2 contains several putative protein-binding motifs, SH3-binding proline-rich regions, and phosphotyrosine sites, but lacks enzymatic motifs. HSH2 was found to interact with cytokine-regulated tyrosine kinase c-FES and an activated Cdc42-associated tyrosine kinase ACK1. HSH2 binds c-FES through both its C-terminal region and its N-terminal region including the SH2 domain and binds ACK1 via its N-terminal proline-rich region. Both kinases bound and tyrosine-phosphorylated HSH2 in mammalian cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136  93 LQHGAAPAWFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESAVTFVLTYRSRTCCRHFLLAQLRDGRHVVLGE 172
Cdd:cd09946     1 LAQDGVPEWFHGAISRE----------AAENMLESQPLGSFLIRVSHSHVGYTLSYKAQSSCRHFMVKLLDDGTFMIPGE 70

                          90       100
                  ....*....|....*....|....*....
gi 2217272136 173 DSAHARLQDLLLHYTAHPLSPYGETLTEP 201
Cdd:cd09946    71 KVAHTSLHALVTFHQQKPIEPRRELLTQA 99

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 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSES-AVTFVLTYRSRT-CCRHFLLAQLRDGRHVVLGEDSAHAR 178
Cdd:cd00173     2 WFHGSISRE----------EAERLLRGKPDGTFLVRESSSePGDYVLSVRSGDgKVKHYLIERNEGGYYLLGGSGRTFPS 71

                  ....*...
gi 2217272136 179 LQDLLLHY 186
Cdd:cd00173    72 LPELVEHY 79

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 2217272136  98 APaWFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESAVTFVLTYRSRTCCRHFLLAQLRDgRHVVLGED-SAH 176
Cdd:cd10351     7 AP-WFHGIISRE----------EAEALLMNATEGSFLVRVSEKIWGYTLSYRLQSGFKHFLVDASGD-FYSFLGVDpNRH 74

                          90       100
                  ....*....|....*....|....*....
gi 2217272136 177 ARLQDLL-LHYTAHPLSPYGETLTEPLAR 204
Cdd:cd10351    75 ATLTDLIdFHKEEIITTSGGELLQEPCGQ 103

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 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESA-VTFVLTYRSRTCCRHFLLAQLRDGRhVVLGEDSA-HAR 178
Cdd:cd09945     3 WYHGAITRI----------EAESLLRPCKEGSYLVRNSESTkQDYSLSLKSAKGFMHMRIQRNETGQ-YILGQFSRpFET 71

                          90
                  ....*....|...
gi 2217272136 179 LQDLLLHYTAHPL 191
Cdd:cd09945    72 IPEMIRHYCLNKL 84

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 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESAVT-FVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSAHARL 179
Cdd:cd10391     3 WYHGSISRA----------EAESRLQPCKEASYLVRNSESGNSkYSIALKTSQGCVHIIVAQTKDNKYTLNQTSAVFDSI 72

                          90
                  ....*....|..
gi 2217272136 180 QDLLLHYTAHPL 191
Cdd:cd10391    73 PEVVHYYSNEKL 84

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        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPK--PQGCYLVRFSESAV-TFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSAHA 177
Cdd:cd09944     7 WFHGGISRD----------EAARLIRQQglVDGVFLVRESQSNPgAFVLSLKHGQKIKHYQIIPIEDEGQWYFTLDDGVT 76

                  ....*.
gi 2217272136 178 RLQDLL 183
Cdd:cd09944    77 KFYDLL 82

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 2217272136 101 WFHGFITRrvrpplsvthREAERLL--EPKPQGCYLVRFSESAV-TFVLTYR-----SRTCCRHFLLAQLRDGRHVVLGE 172
Cdd:cd09933     5 WFFGKIKR----------KDAEKLLlaPGNPRGTFLIRESETTPgAYSLSVRdgddaRGDTVKHYRIRKLDNGGYYITTR 74

                          90
                  ....*....|....*..
gi 2217272136 173 dSAHARLQDLLLHYTAH 189
Cdd:cd09933    75 -ATFPTLQELVQHYSKD 90

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 2217272136 101 WFHGFITRrvrpplsvthREAERLLEPKPQ-GCYLVRFSESAV-TFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDSaHAR 178
Cdd:cd09931     2 WFHGHLSG----------KEAEKLLLEKGKpGSFLVRESQSKPgDFVLSVRTDDDKVTHIMIRCQGGKYDVGGGEE-FDS 70

                          90
                  ....*....|...
gi 2217272136 179 LQDLLLHYTAHPL 191
Cdd:cd09931    71 LTDLVEHYKKNPM 83

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; 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        40
                  ....*....|....*....|....*....|....*....|...
gi 2217272136 120 EAERLLEPKPQGCYLVRFSES-AVTFVLTYRSRTCCRHFLLAQ 161
Cdd:cd10388    21 DAEKVLSNKPDGSFLVRDSSDdRYIFSLSFRSQGSVHHTRIEQ 63

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb14 is part of the Grb7 family of proteins which also includes Grb7, 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. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR) and weakly to the erbB2 receptor. 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 2217272136  95 HGAAPaWFHGFITRRvrpplsvthrEAERLLEPKP--QGCYLVRFSES-AVTFVLTYRSRTCCRHFLLAQLRDGRHVVLG 171
Cdd:cd10414     2 HRSQP-WFHHKISRD----------EAQRLIIQQGlvDGVFLVRDSQSnPRTFVLSMSHGQKIKHFQIIPVEDDGELFHT 70

                          90
                  ....*....|..
gi 2217272136 172 EDSAHARLQDLL 183
Cdd:cd10414    71 LDDGHTRFTDLI 82

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 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSE 139
Cdd:cd09923     2 WYWGGITRY----------EAEELLAGKPEGTFLVRDSS 30

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110alpha, and 3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 101 WFHGFITRRvrpplsvthrEAERLLEPKPQGCYLVRFSESAVTFVLTYRSRTCCRHFLLAQLRDGRHVVLGEDsAHARLQ 180
Cdd:cd09930     8 WLVGDINRT----------QAEELLRGKPDGTFLIRESSTQGCYACSVVCNGEVKHCVIYKTETGYGFAEPYN-LYESLK 76

                          90       100
                  ....*....|....*....|...
gi 2217272136 181 DLLLHYTAHPLSPYGETLTEPLA 203
Cdd:cd09930    77 ELVLHYAHNSLEQHNDSLTVTLA 99

sporozoite surface protein 2 (SSP2); Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217272136 218 ESNFGSKSQDPNPQYSPIIkqgqaPVPMQKEGaGEKEPSQLLRPKPPIPAKPQLPPEVYTIPVPRHRPAPRPKPSNP--- 294
Cdd:PTZ00441  343 EENLFPPGDDEVPDESNVP-----PNPPNVPG-GSNSEFSSDVENPPNPPNPDIPEQEPNIPEDSNKEVPEDVPMEPedd 416

                          90
                  ....*....|.
gi 2217272136 295 ---IYNEPDEP 302
Cdd:PTZ00441  417 rdnNFNEPKKP 427