BCR downstream signaling 1 Pleckstrin homology (PH) domain; Brdg1 is thought to function as a docking protein acting downstream of Tec, a protein tyrosine kinases (PTK), in B-cell antigen receptor (BCR) signaling. BRDG1 contains a proline-rich (PR) motif which is thought to bind SH3 or WW domains, a PH domain, and multiple tyrosine residues which are potential target sites for SH2 domains. Since PH domains bind phospholipids it is thought to be involved in the tethering of Tec and BRDG1 to the cell membrane.Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induces phosphorylation of BRDG1 on tyrosine residues. Efficient phosphorylation requires both the PH and SH2 domains of BRDG1 and the kinase domain of Tec. The overexpression of BRDG1 increases theBCR-mediated activation of cAMP-response element binding protein (CREB). Phosphorylated BRDG1 is hypothesized to recruit CREB either directly or through its recruitment of downstream effectors which then recruit CREB. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62243734   9 RVPKPKGVLPSHYYESFLEKKGPCDRDYKKFWAGLQGLTIYFYNSNRDFQHVEKLNLGAFEKLTDEIPWGSSRDPgTHFS 88
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDA-ARFT 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 62243734  89 LILRDQEIKFKVETLECREMWKGFILTVVELRVPTDLTLLPGHLYMMS 136
Cdd:cd13268  80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

BCR downstream signaling 1 Pleckstrin homology (PH) domain; Brdg1 is thought to function as a docking protein acting downstream of Tec, a protein tyrosine kinases (PTK), in B-cell antigen receptor (BCR) signaling. BRDG1 contains a proline-rich (PR) motif which is thought to bind SH3 or WW domains, a PH domain, and multiple tyrosine residues which are potential target sites for SH2 domains. Since PH domains bind phospholipids it is thought to be involved in the tethering of Tec and BRDG1 to the cell membrane.Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induces phosphorylation of BRDG1 on tyrosine residues. Efficient phosphorylation requires both the PH and SH2 domains of BRDG1 and the kinase domain of Tec. The overexpression of BRDG1 increases theBCR-mediated activation of cAMP-response element binding protein (CREB). Phosphorylated BRDG1 is hypothesized to recruit CREB either directly or through its recruitment of downstream effectors which then recruit CREB. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62243734   9 RVPKPKGVLPSHYYESFLEKKGPCDRDYKKFWAGLQGLTIYFYNSNRDFQHVEKLNLGAFEKLTDEIPWGSSRDPgTHFS 88
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDA-ARFT 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 62243734  89 LILRDQEIKFKVETLECREMWKGFILTVVELRVPTDLTLLPGHLYMMS 136
Cdd:cd13268  80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62243734   156 KVSRLEA-QLLLERYPEcGNLLLRPSGDGADGVSVTTRqmHNGthVVRHYKVKREGP-KYVIDVEQPFSctSLDAVVNYF 233
Cdd:pfam00017   5 KISRQEAeRLLLNGKPD-GTFLVRESESTPGGYTLSVR--DDG--KVKHYKIQSTDNgGYYISGGVKFS--SLAELVEHY 77

BCR downstream signaling 1 Pleckstrin homology (PH) domain; Brdg1 is thought to function as a docking protein acting downstream of Tec, a protein tyrosine kinases (PTK), in B-cell antigen receptor (BCR) signaling. BRDG1 contains a proline-rich (PR) motif which is thought to bind SH3 or WW domains, a PH domain, and multiple tyrosine residues which are potential target sites for SH2 domains. Since PH domains bind phospholipids it is thought to be involved in the tethering of Tec and BRDG1 to the cell membrane.Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induces phosphorylation of BRDG1 on tyrosine residues. Efficient phosphorylation requires both the PH and SH2 domains of BRDG1 and the kinase domain of Tec. The overexpression of BRDG1 increases theBCR-mediated activation of cAMP-response element binding protein (CREB). Phosphorylated BRDG1 is hypothesized to recruit CREB either directly or through its recruitment of downstream effectors which then recruit CREB. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62243734   9 RVPKPKGVLPSHYYESFLEKKGPCDRDYKKFWAGLQGLTIYFYNSNRDFQHVEKLNLGAFEKLTDEIPWGSSRDPgTHFS 88
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDA-ARFT 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 62243734  89 LILRDQEIKFKVETLECREMWKGFILTVVELRVPTDLTLLPGHLYMMS 136
Cdd:cd13268  80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

Src homology 2 domain found in Signal-transducing adaptor protein (STAP) family; STAP1 and STAP2 are signal-transducing adaptor proteins. They are composed of a Pleckstrin homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an ortholog of BRDG1 (BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity. STAP1 has been shown to interact with C19orf2, an unconventional prefoldin RPB5 interactor. The STAP2 protein is the substrate of breast tumor kinase, an Src-type non-receptor tyrosine kinase that mediates the interactions linking proteins involved in signal transduction pathways. STAP2 has alternative splicing variants. STAP2 has been shown to interact with tyrosine-protein kinase 6 (PTK6). 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 62243734 151 PSCFLKVSRLEAQLLLERYPECGNLLLRPSGDGaDGVSVTTRQMHNGtHVVRHYKVKREGPKYVIDVEQPFSCTSLDAVV 230
Cdd:cd09939   1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDS-RNYSVTTRQEINI-PVIRHYKVMSVGQNYTIELEKPVTCPNLFSVI 78

                        90
                ....*....|....*.
gi 62243734 231 NYFVSHTKKALVPFLL 246
Cdd:cd09939  79 NYFVKETRGNLRPFIL 94

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 62243734 157 VSRLEAQLLLERYPECGNLLLRPSGDGADGVSVTTRQmhNGThvVRHYKVKREGPKYVIDVEQPFsctSLDAVVNYFVSH 236
Cdd:cd09932  11 LTREQAEEMLMRVPRDGAFLVRPSETDPNSFAISFRA--EGK--IKHCRIKQEGRLFVIGTSQFE---SLVELVSYYEKH 83

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62243734   156 KVSRLEA-QLLLERYPEcGNLLLRPSGDGADGVSVTTRqmHNGthVVRHYKVKREGP-KYVIDVEQPFSctSLDAVVNYF 233
Cdd:pfam00017   5 KISRQEAeRLLLNGKPD-GTFLVRESESTPGGYTLSVR--DDG--KVKHYKIQSTDNgGYYISGGVKFS--SLAELVEHY 77