Src homology 2 (SH2) domain found in cytokine-inducible SH2-containing protein (CIS); CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of the CIS gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Suppressor of cytokine signalling (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. 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 390407759  58 LENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSPARPTLSSFPNV 137
Cdd:cd10718    1 LRESGWYWGSITASEAHQALQKAPEGTFLVRDSSHPSYMLTLSVKTTRGPTNVRIEYSDGSFRLDSSSLARPRLLSFPDV 80

                 ....*...
gi 390407759 138 PSLVQHYM 145
Cdd:cd10718   81 VSLVQHYV 88

Src homology 2 (SH2) domain found in cytokine-inducible SH2-containing protein (CIS); CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of the CIS gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Suppressor of cytokine signalling (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. 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 390407759  58 LENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSPARPTLSSFPNV 137
Cdd:cd10718    1 LRESGWYWGSITASEAHQALQKAPEGTFLVRDSSHPSYMLTLSVKTTRGPTNVRIEYSDGSFRLDSSSLARPRLLSFPDV 80

                 ....*...
gi 390407759 138 PSLVQHYM 145
Cdd:cd10718   81 VSLVQHYV 88

The SOCS box acts as a bridge between specific substrate- binding domains and more generic proteins that comprise a large family of E3 ubiquitin protein ligases;

                           10        20        30
                   ....*....|....*....|....*....|....
gi 390407759   189 PSLQHLTRLVINRHSDCPEQLPLPRPLLRYVQDY 222
Cdd:smart00969   1 RSLQHLCRLAIRRSLGGIDKLPLPPRLKDYLLYY 34

SH2 domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 390407759   77 LQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLldssspARPTLSSFPNVPSLVQHY 144
Cdd:pfam00017  16 LNGKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQSTDNGGY------YISGGVKFSSLAELVEHY 77

Src homology 2 (SH2) domain found in cytokine-inducible SH2-containing protein (CIS); CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of the CIS gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Suppressor of cytokine signalling (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. 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 390407759  58 LENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSPARPTLSSFPNV 137
Cdd:cd10718    1 LRESGWYWGSITASEAHQALQKAPEGTFLVRDSSHPSYMLTLSVKTTRGPTNVRIEYSDGSFRLDSSSLARPRLLSFPDV 80

                 ....*...
gi 390407759 138 PSLVQHYM 145
Cdd:cd10718   81 VSLVQHYV 88

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        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 390407759  62 GWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSPARPtlsSFPNVPSLV 141
Cdd:cd09923    1 GWYWGGITRYEAEELLAGKPEGTFLVRDSSDSRYLFSVSFRTYGRTLHARIEYSNGRFSFDSSDPSVP---RFPCVVELI 77

                 ....
gi 390407759 142 QHYM 145
Cdd:cd09923   78 EHYV 81

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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 390407759  57 YLENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSparptlSSFPN 136
Cdd:cd10382    6 MLDASGFYWGPLSVEEAHAKLKREPVGTFLIRDSRQKNCFFALSVKMASGPVSIRILFKAGKFSLDGSK------ESFDC 79

                         90
                 ....*....|....
gi 390407759 137 VPSLVQHYMGPERQ 150
Cdd:cd10382   80 LFKLLEHYVASPKK 93

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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 390407759  52 ASNFCYLENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLLDSSSPAR--- 128
Cdd:cd10388    1 TASLRELKDCGWYWGPMSWEDAEKVLSNKPDGSFLVRDSSDDRYIFSLSFRSQGSVHHTRIEQYQGTFSLGSRNKFVdrs 80

                 ....*.
gi 390407759 129 PTLSSF 134
Cdd:cd10388   81 QSLVEF 86

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 390407759  63 WYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARG-PTSIRIQYSGAMFLLDSSSPARptlssFPNVPSLV 141
Cdd:cd00173    2 WFHGSISREEAERLLRGKPDGTFLVRESSSEPGDYVLSVRSGDGkVKHYLIERNEGGYYLLGGSGRT-----FPSLPELV 76

                 ...
gi 390407759 142 QHY 144
Cdd:cd00173   77 EHY 79

SOCS (suppressors of cytokine signaling) box of CIS (cytokine-inducible SH2 protein) 1-like proteins. Together with the SOCS proteins, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. CIS1, like SOCS1 and SOCS3, is involved in the down-regulation of the JAK/STAT pathway. CIS1 binds to cytokine receptors at STAT5-docking sites, which prohibits recruitment of STAT5 to the receptor signaling complex and results in the down-regulation of activation by STAT5.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 390407759 188 LPSLQHLTRLVINRHSDCPEQLPLPRPLLRYVQDYPFKV 226
Cdd:cd03734    3 ARSLQHLCRLVINRLVTDVDCLPLPRRMADYLRQYPFQL 41

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 390407759  62 GWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYS--GAMFLLDSSSParptlssFPNVPS 139
Cdd:cd09945    2 GWYHGAITRIEAESLLRPCKEGSYLVRNSESTKQDYSLSLKSAKGFMHMRIQRNetGQYILGQFSRP-------FETIPE 74

                 ....*
gi 390407759 140 LVQHY 144
Cdd:cd09945   75 MIRHY 79

SH2 domain;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 390407759   77 LQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRIQYSGAMFLldssspARPTLSSFPNVPSLVQHY 144
Cdd:pfam00017  16 LNGKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQSTDNGGY------YISGGVKFSSLAELVEHY 77

N-terminal Src homology 2 (nSH2) 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, an internal 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
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 390407759  58 LENSGWYWGAVTAAQAHAALQEASEGAFLVRDSSHPLYMLTLSVRTARGPTSIRI 112
Cdd:cd09942    4 LQEAEWYWGDISREEVNEKMRDTPDGTFLVRDASTMKGDYTLTLRKGGNNKLIKI 58

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 390407759  78 QEASEGAFLVRDSSHpLYMLTLSVRT-ARGPTSIRIQY-------SGAMFLLDSssparptlSSFPNVPSLVQHY 144
Cdd:cd10398   24 QESKEGAFIVRDSRH-LGSYTISVFTrARRSTEASIKHyqikkndSGQWYVAER--------HLFQSIPELIQYH 89

SOCS box; The SOCS box acts as a bridge between specific substrate- binding domains and more generic proteins that comprise a large family of E3 ubiquitin protein ligases.

                          10        20        30
                  ....*....|....*....|....*....|....*..
gi 390407759  189 PSLQHLTRLVINRH-----SDCPEQLPLPRPLLRYVQ 220
Cdd:pfam07525   3 RSLQHLCRLAIRRAlgkrrLGAIDKLPLPPLLKDYLL 39

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 390407759  78 QEASEGAFLVR--DSSHPLYmlTLSVRTARGPTSIRIQYSGAMFLLDSSsparptlSSFPNVPSLVQHYMGPERQAEE-- 153
Cdd:cd10340   18 TRGVDGSFLARpsKSNPGDF--TLSVRRGDEVTHIKIQNTGDYYDLYGG-------EKFATLSELVQYYMEQHGQLREkn 88

                 ....*
gi 390407759 154 GKVVE 158
Cdd:cd10340   89 GDVIE 93

SOCS (suppressors of cytokine signaling) box of SOCS7-like proteins. Together with CIS1, the CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. SOCS7 is important in the functioning of neuronal cells. The general function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

                         10        20        30
                 ....*....|....*....|....*....|..
gi 390407759 190 SLQHLTRLVINR--HSDCPEQLPLPRPLLRYV 219
Cdd:cd03741    5 SLQHLCRFVIRKlvRRDHIPALPLPRRLIDYL 36

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 390407759  83 GAFLVRDSSHPLYMLTLSVR---TARGPT----SIRIQYSGAMFLLdsssparpTLSSFPNVPSLVQHYMG 146
Cdd:cd09933   27 GTFLIRESETTPGAYSLSVRdgdDARGDTvkhyRIRKLDNGGYYIT--------TRATFPTLQELVQHYSK 89

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 390407759  58 LENSGWYWGAVTAAQAHAALQEasEGAFLVRDSSHPLYMLTLSVRTARGPTSIRI---------QYSGAMFLLDSSSpar 128
Cdd:cd10337    3 LRSHAWYHGRIPRQVAESLVQR--EGDFLVRDSLSSPGDYVLTCRWKGQPLHFKInrvvlrpseAYTRVQYQFEDEQ--- 77

                         90       100
                 ....*....|....*....|.
gi 390407759 129 ptlssFPNVPSLVQHYMGPER 149
Cdd:cd10337   78 -----FDSIPALVHFYVGNRR 93