SH2B adapter protein 1, 2, and 3 Pleckstrin homology (PH) domain; SH2B family/APS proteins are a family of intracellular adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases (RTKs) including receptors for insulin, insulin-like growth factor-1, Janus kinase 2 (Jak2), platelet derived growth factor, fibroblast growth factor and nerve growth factor. They function in glucose homeostasis, energy metabolism, hematopoesis and reproduction. Mutations in human SH2B orthologs are associated with metabolic disregulation and obesity. There are several SH2B members in mammals: SH2B1 (splice variants: SH2B1alpha, SH2B1beta, SH2B1gamma, and SH2B1delta), SH2B2 (APS) and SH2B3 (Lnk). They contain a PH domain, a SH2 domain, a proline rich region, multiple consensus sites for tyrosine and serine/threonine phosphorylation and a highly conserved c-Cbl recognition motif. These domains function as protein-protein interaction motifs which allows SH2B proteins to integrate and transduce intracellular signals from multiple signaling networks in the absence of intrinsic catalytic activity. SH2B proteins bind via their SH2 domains to phosphotyrosine residues within the intracellular tails of several activated RTKs thereby contributing to receptor activation. SH2B proteins have been shown to interact with insulin receptor substrates IRS1 and IRS2, Grb2, Shc and c-Cbl which may or may not require RTK-stimulated tyrosine phosphorylation of SH2B. positively and negatively regulating RTK signaling. Understanding the physiological functions of SH2B proteins in mammals has been complicated by the presence of multiple SH2B isoforms and conflicting data. Both SH2-Bbeta and APS associate with JAKs, but the former facilitates JAK/STAT signaling while the latter inhibits it. Lnk plays a role in cell growth and proliferation with mutations resulting in growth reduction, developmental delay and female sterility. Recently Lnk Drosophila has been shown to be an important regulator of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway during growth. 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 728050530 186 DIQREGALRFMVADDAASGpgGTAQWQKCRLLLRRAVAGER-FRLEFFVPPKASRPKVSIPLSAIIEVRTTMPLEMPEKD 264
Cdd:cd01231    1 ECRKEGIVNYLSGEETASD--GGPRWQKCRLVLVKAAGGEGeYLLEFYVPPKSSKPKLGIFCSLIQEVRETTALEMPDNE 78

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 728050530 265 NTFVLKVENGAEYILETIDSLQKHSWVADIQGCVDPG 301
Cdd:cd01231   79 NTFVLKVENSTEYIIEAGDEQQMRSWLAEIRECMSPG 115

SH2B adapter protein 1, 2, and 3 Pleckstrin homology (PH) domain; SH2B family/APS proteins are a family of intracellular adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases (RTKs) including receptors for insulin, insulin-like growth factor-1, Janus kinase 2 (Jak2), platelet derived growth factor, fibroblast growth factor and nerve growth factor. They function in glucose homeostasis, energy metabolism, hematopoesis and reproduction. Mutations in human SH2B orthologs are associated with metabolic disregulation and obesity. There are several SH2B members in mammals: SH2B1 (splice variants: SH2B1alpha, SH2B1beta, SH2B1gamma, and SH2B1delta), SH2B2 (APS) and SH2B3 (Lnk). They contain a PH domain, a SH2 domain, a proline rich region, multiple consensus sites for tyrosine and serine/threonine phosphorylation and a highly conserved c-Cbl recognition motif. These domains function as protein-protein interaction motifs which allows SH2B proteins to integrate and transduce intracellular signals from multiple signaling networks in the absence of intrinsic catalytic activity. SH2B proteins bind via their SH2 domains to phosphotyrosine residues within the intracellular tails of several activated RTKs thereby contributing to receptor activation. SH2B proteins have been shown to interact with insulin receptor substrates IRS1 and IRS2, Grb2, Shc and c-Cbl which may or may not require RTK-stimulated tyrosine phosphorylation of SH2B. positively and negatively regulating RTK signaling. Understanding the physiological functions of SH2B proteins in mammals has been complicated by the presence of multiple SH2B isoforms and conflicting data. Both SH2-Bbeta and APS associate with JAKs, but the former facilitates JAK/STAT signaling while the latter inhibits it. Lnk plays a role in cell growth and proliferation with mutations resulting in growth reduction, developmental delay and female sterility. Recently Lnk Drosophila has been shown to be an important regulator of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway during growth. 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 728050530 186 DIQREGALRFMVADDAASGpgGTAQWQKCRLLLRRAVAGER-FRLEFFVPPKASRPKVSIPLSAIIEVRTTMPLEMPEKD 264
Cdd:cd01231    1 ECRKEGIVNYLSGEETASD--GGPRWQKCRLVLVKAAGGEGeYLLEFYVPPKSSKPKLGIFCSLIQEVRETTALEMPDNE 78

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 728050530 265 NTFVLKVENGAEYILETIDSLQKHSWVADIQGCVDPG 301
Cdd:cd01231   79 NTFVLKVENSTEYIIEAGDEQQMRSWLAEIRECMSPG 115

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 728050530   187 IQREGALRFMvaddaasGPGGTAQWQKCRLLLRRavagerFRLEFFVPPKA---SRPKVSIPLSAIiEVRTTMPLEMPEK 263
Cdd:smart00233   1 VIKEGWLYKK-------SGGGKKSWKKRYFVLFN------STLLYYKSKKDkksYKPKGSIDLSGC-TVREAPDPDSSKK 66

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 728050530   264 DNTFVLKVENGAEYILETIDSLQKHSWVADIQGCVD 299
Cdd:smart00233  67 PHCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

SH2B adapter protein 1, 2, and 3 Pleckstrin homology (PH) domain; SH2B family/APS proteins are a family of intracellular adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases (RTKs) including receptors for insulin, insulin-like growth factor-1, Janus kinase 2 (Jak2), platelet derived growth factor, fibroblast growth factor and nerve growth factor. They function in glucose homeostasis, energy metabolism, hematopoesis and reproduction. Mutations in human SH2B orthologs are associated with metabolic disregulation and obesity. There are several SH2B members in mammals: SH2B1 (splice variants: SH2B1alpha, SH2B1beta, SH2B1gamma, and SH2B1delta), SH2B2 (APS) and SH2B3 (Lnk). They contain a PH domain, a SH2 domain, a proline rich region, multiple consensus sites for tyrosine and serine/threonine phosphorylation and a highly conserved c-Cbl recognition motif. These domains function as protein-protein interaction motifs which allows SH2B proteins to integrate and transduce intracellular signals from multiple signaling networks in the absence of intrinsic catalytic activity. SH2B proteins bind via their SH2 domains to phosphotyrosine residues within the intracellular tails of several activated RTKs thereby contributing to receptor activation. SH2B proteins have been shown to interact with insulin receptor substrates IRS1 and IRS2, Grb2, Shc and c-Cbl which may or may not require RTK-stimulated tyrosine phosphorylation of SH2B. positively and negatively regulating RTK signaling. Understanding the physiological functions of SH2B proteins in mammals has been complicated by the presence of multiple SH2B isoforms and conflicting data. Both SH2-Bbeta and APS associate with JAKs, but the former facilitates JAK/STAT signaling while the latter inhibits it. Lnk plays a role in cell growth and proliferation with mutations resulting in growth reduction, developmental delay and female sterility. Recently Lnk Drosophila has been shown to be an important regulator of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway during growth. 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 728050530 186 DIQREGALRFMVADDAASGpgGTAQWQKCRLLLRRAVAGER-FRLEFFVPPKASRPKVSIPLSAIIEVRTTMPLEMPEKD 264
Cdd:cd01231    1 ECRKEGIVNYLSGEETASD--GGPRWQKCRLVLVKAAGGEGeYLLEFYVPPKSSKPKLGIFCSLIQEVRETTALEMPDNE 78

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 728050530 265 NTFVLKVENGAEYILETIDSLQKHSWVADIQGCVDPG 301
Cdd:cd01231   79 NTFVLKVENSTEYIIEAGDEQQMRSWLAEIRECMSPG 115

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 728050530   187 IQREGALRFMvaddaasGPGGTAQWQKCRLLLRRavagerFRLEFFVPPKA---SRPKVSIPLSAIiEVRTTMPLEMPEK 263
Cdd:smart00233   1 VIKEGWLYKK-------SGGGKKSWKKRYFVLFN------STLLYYKSKKDkksYKPKGSIDLSGC-TVREAPDPDSSKK 66

                           90       100       110
                   ....*....|....*....|....*....|....*.
gi 728050530   264 DNTFVLKVENGAEYILETIDSLQKHSWVADIQGCVD 299
Cdd:smart00233  67 PHCFEIKTSDRKTLLLQAESEEEREKWVEALRKAIA 102

Pleckstrin homology (PH) domain; 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 728050530 189 REGALRFMvaddaasGPGGTAQWQKCRLLLRRavagerFRLEFFVPPKA--SRPKVSIPLSAIIEVRTTMPlemPEKDNT 266
Cdd:cd00821    1 KEGYLLKR-------GGGGLKSWKKRWFVLFE------GVLLYYKSKKDssYKPKGSIPLSGILEVEEVSP---KERPHC 64

                         90       100
                 ....*....|....*....|....*...
gi 728050530 267 FVLKVENGAEYILETIDSLQKHSWVADI 294
Cdd:cd00821   65 FELVTPDGRTYYLQADSEEERQEWLKAL 92