2hdx

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]} [JAK2_MOUSE] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.^{[5] [6] [7] [8] [9] [10] [11] [12]}

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. ↑ Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell. 2001 Dec;8(6):1327-38. PMID:11779507
6. ↑ Guilluy C, Bregeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med. 2010 Feb;16(2):183-90. doi: 10.1038/nm.2079. Epub 2010 Jan 24. PMID:20098430 doi:10.1038/nm.2079
7. ↑ Jakel H, Weinl C, Hengst L. Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control. Oncogene. 2011 Aug 11;30(32):3502-12. doi: 10.1038/onc.2011.68. Epub 2011 Mar 21. PMID:21423214 doi:10.1038/onc.2011.68
8. ↑ Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227-36. PMID:8343951
9. ↑ Nakamura N, Chin H, Miyasaka N, Miura O. An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells. J Biol Chem. 1996 Aug 9;271(32):19483-8. PMID:8702638
10. ↑ Yamashita Y, Watanabe S, Miyazato A, Ohya Ki, Ikeda U, Shimada K, Komatsu N, Hatake K, Miura Y, Ozawa K, Mano H. Tec and Jak2 kinases cooperate to mediate cytokine-driven activation of c-fos transcription. Blood. 1998 Mar 1;91(5):1496-507. PMID:9473212
11. ↑ Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998 May 1;93(3):385-95. PMID:9590173
12. ↑ Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998 May 1;93(3):397-409. PMID:9590174
13. ↑ 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