2hdv

Structural highlights

Function

[SH2B1_MOUSE] Adapter protein for several members of the tyrosine kinase receptor family. Involved in multiple signaling pathways mediated by Janus kinase (JAK) and receptor tyrosine kinases, including the receptors of insulin (INS), insulin-like growth factor I (IGF1), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF) and fibroblast growth factors (FGFs). In growth hormone (GH) signaling, autophosphorylated ('Tyr-813') JAK2 recruits SH2B1, which in turn is phosphorylated by JAK2 on tyrosine residues. These phosphotyrosines form potential binding sites for other signaling proteins. GH also promotes serine/threonine phosphorylation of SH2B1 and these phosphorylated residues may serve to recruit other proteins to the GHR-JAK2-SH2B1 complexes, such as RAC1. In leptin (LEP) signaling, binds to and potentiates the activation of JAK2 by globally enhancing downstream pathways. In response to leptin, binds simultaneously to both, JAK2 and IRS1 or IRS2, thus mediating formation of a complex of JAK2, SH2B1 and IRS1 or IRS2. Mediates tyrosine phosphorylation of IRS1 and IRS2, resulting in activation of the PI 3-kinase pathway. Acts as positive regulator of NGF-mediated activation of the Akt/Forkhead pathway; prolongs NGF-induced phosphorylation of AKT1 on 'Ser-473' and AKT1 enzymatic activity. Enhances the kinase activity of the cytokine receptor-associated tyrosine kinase JAK2 and of other receptor tyrosine kinases, such as FGFR3 and NTRK1. For JAK2, the mechanism seems to involve dimerization of both, SH2B1 and JAK2. Enhances RET phosphorylation and kinase activity (By similarity). Isoforms seem to be differentially involved in IGF-I and PDGF-induced mitogenesis, according the order: isoform 3 > isoform 4 > isoform 1 > isoform 2.^{[1] [2] [3] [4]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Yousaf N, Deng Y, Kang Y, Riedel H. Four PSM/SH2-B alternative splice variants and their differential roles in mitogenesis. J Biol Chem. 2001 Nov 2;276(44):40940-8. Epub 2001 Aug 13. PMID:11502739 doi:http://dx.doi.org/10.1074/jbc.M104191200
2. ↑ Duan C, Li M, Rui L. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. J Biol Chem. 2004 Oct 15;279(42):43684-91. Epub 2004 Aug 16. PMID:15316008 doi:http://dx.doi.org/10.1074/jbc.M408495200
3. ↑ Ren D, Li M, Duan C, Rui L. Identification of SH2-B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metab. 2005 Aug;2(2):95-104. PMID:16098827 doi:http://dx.doi.org/S1550-4131(05)00203-2
4. ↑ Rui L, Mathews LS, Hotta K, Gustafson TA, Carter-Su C. Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Mol Cell Biol. 1997 Nov;17(11):6633-44. PMID:9343427
5. ↑ Hu J, Hubbard SR. Structural basis for phosphotyrosine recognition by the Src homology-2 domains of the adapter proteins SH2-B and APS. J Mol Biol. 2006 Aug 4;361(1):69-79. Epub 2006 Jun 16. PMID:16824542 doi:10.1016/j.jmb.2006.05.070