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
                ....*....|....*....|....*....|....*....|....*....|....
gi 71993809 192 TPNML-AC--YHGPLSHEDACRQLVLP--GEFIIRDSSMRGE-FAVSYKTSHGP 239
Cdd:cd10382   3 TSAMLdASgfYWGPLSVEEAHAKLKREpvGTFLIRDSRQKNCfFALSVKMASGP 56

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
                ....*....|....*....|....*....|....*....|....*....|....
gi 71993809 192 TPNML-AC--YHGPLSHEDACRQLVLP--GEFIIRDSSMRGE-FAVSYKTSHGP 239
Cdd:cd10382   3 TSAMLdASgfYWGPLSVEEAHAKLKREpvGTFLIRDSRQKNCfFALSVKMASGP 56

Phosphotyrosine interaction domain (PTB/PID);

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71993809    27 FAVKYMGYapiLQTIRER--PIADRDALVRHCINTVvssRATHEYSVIQHEGVVGPYVSVYqldlfLNISSFTITCFHIQ 104
Cdd:pfam00640   1 FAVRYLGS---VEVPEERapDKNTRMQQAREAIRRV---KAAKINKIRGLSGETGPGTKVD-----LFISTDGLKLLNPD 69

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 71993809   105 DGRT---HLLGRyknnqISHYKYREIDGRHYLGIVMKIGRTEKRECNVFM 151
Cdd:pfam00640  70 TQELihdHPLVS-----ISFCADGDPDLMRYFAYIARDKATNKFACHVFE 114

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
                ....*....|....*....|....*....|....*....|....*....|....
gi 71993809 192 TPNML-AC--YHGPLSHEDACRQLVLP--GEFIIRDSSMRGE-FAVSYKTSHGP 239
Cdd:cd10382   3 TSAMLdASgfYWGPLSVEEAHAKLKREpvGTFLIRDSRQKNCfFALSVKMASGP 56

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
                   ....*....|....*....|....*....|....*....|.
gi 71993809    198 CYHGPLSHEDACRQLVL--PGEFIIRDS-SMRGEFAVSYKT 235
Cdd:smart00252   3 WYHGFISREEAEKLLKNegDGDFLVRDSeSSPGDYVLSVRV 43

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
                ....*....|....*....|....*....|....*....
gi 71993809 199 YHGPLSHEDACRQLVLP----GEFIIRDS-SMRGEFAVS 232
Cdd:cd10369   6 FFGAIKRADAEKQLLYSenqtGAFLIRESeSQKGEFSLS 44

Shc-like phosphotyrosine-binding (PTB) domain; Shc is a substrate for receptor tyrosine kinases, which can interact with phosphoproteins at NPXY motifs. Shc contains an PTB domain followed by an SH2 domain. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This cd is part of the Shc-like subgroup.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 71993809  13 WGESAKHVNASGDRFAVKYMGYAPILQTIRERPIADRDALVRHCINTV 60
Cdd:cd01209   3 WLHPDQLGMGPGVSYPVRYVGCIEVLQSMRSLDFNTRTQVTREAINRV 50