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SH2B1  -  SH2B adaptor protein 1

Homo sapiens

Synonyms: FLJ30542, KIAA1299, PSM, Pro-rich, PH and SH2 domain-containing signaling mediator, SH2 domain-containing protein 1B, ...
 
 
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Disease relevance of SH2B1

  • Additionally, the chromosomal location of the SH2-B gene was determined to be the distal arm of mouse Chromosome (Chr) 7 in a region linked to obesity in mice [1].
  • APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice [2].
 

High impact information on SH2B1

  • SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor [3].
  • Moreover, rAPS and SH2-B bind to Grb2, and both are sufficient to mediate NGF induction of Ras, MAP kinase (MAPK), and morphological differentiation of PC12 cells [4].
  • Antibody perturbation and transient transfection experiments indicate that SH2-B, or a closely related molecule, is necessary for NGF-dependent signaling in neonatal sympathetic neurons [4].
  • Kinase activation through dimerization by human SH2-B [5].
  • At lower levels of SH2-B or APS expression, dimerization approximates two JAK2 molecules to induce transactivation [5].
  • SH2B1 localizes to focal adhesions to regulate focal adhesion size and number [6].
 

Chemical compound and disease context of SH2B1

 

Biological context of SH2B1

 

Anatomical context of SH2B1

  • Female knockout mice possess small, anovulatory ovaries with reduced numbers of follicles and male SH2-B(-/-) mice have small testes with a reduced number of sperm [12].
  • Rudd discusses the role of Lnk in B cells and hypothesizes a mechanism whereby Lnk, and its closely related protein family members, the adaptor molecules containing pleckstrin homology (PH) and Src-homology 2 (SH2) domains (APS), and Src-homology 2-B protein (SH2-B), may mediate signal promotion or attenuation [13].
  • In addition to SH2-B alpha, the expression of three SH2-B alternative splice variants, SH2-B beta, gamma and delta, was detected in human cell lines [14].
 

Associations of SH2B1 with chemical compounds

  • Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta [15].
  • Structural basis for phosphotyrosine recognition by the Src homology-2 domains of the adapter proteins SH2-B and APS [16].
  • To gain insight into the mechanism by which the adapter protein SH2-B promotes nerve growth factor (NGF)-mediated neuronal differentiation and survival, the effect of SH2-B on the serine/threonine kinase Akt/protein kinase B and downstream effector proteins was examined [17].
  • These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice [2].
 

Regulatory relationships of SH2B1

  • In this study, we demonstrate the existence of an additional binding site(s) for JAK2 within the N-terminal region of SH2-Bbeta (amino acids 1 to 555) and the ability of this region of SH2-B to inhibit JAK2 [18].
 

Other interactions of SH2B1

  • We isolated c-Abl as a TrkA-interacting protein, in addition to known proteins such as phospholipase Cgamma and SH2-B [19].
  • Similarly, JAK2 is present in alphaSH2-B immunoprecipitates in the absence and presence of GH, with GH substantially increasing the coprecipitation of JAK2 with SH2-B [18].
  • Because of its other potential protein-protein interaction domains and its recruitment and phosphorylation by kinases that are not activated by SH2-B, SH2-B is thought likely to mediate other, more-specific actions of GH, as yet to be determined [10].
  • Structure-function analyses revealed that the SH2-B multimerization domain resides within its amino terminus, which is necessary for SH2-B-mediated nerve growth factor (NGF) signaling [20].
  • Using x-ray crystallography, site-directed mutagenesis, and calorimetric studies, we have characterized the interaction between the Cbl TKB domain and the Cbl recruitment site in APS, which contains a sequence motif, RA(V/I)XNQpY(S/T), that is conserved in the related adapter proteins SH2-B and Lnk [21].
 

Analytical, diagnostic and therapeutic context of SH2B1

  • Gene therapy or investigating the genetic component of obesity specifically related to SH2-B might be a more worthwhile approach to treat the obese [22].

References

  1. Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain. Nelms, K., O'Neill, T.J., Li, S., Hubbard, S.R., Gustafson, T.A., Paul, W.E. Mamm. Genome (1999) [Pubmed]
  2. Differential role of SH2-B and APS in regulating energy and glucose homeostasis. Li, M., Ren, D., Iseki, M., Takaki, S., Rui, L. Endocrinology (2006) [Pubmed]
  3. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. Ren, D., Zhou, Y., Morris, D., Li, M., Li, Z., Rui, L. J. Clin. Invest. (2007) [Pubmed]
  4. Identification and characterization of novel substrates of Trk receptors in developing neurons. Qian, X., Riccio, A., Zhang, Y., Ginty, D.D. Neuron (1998) [Pubmed]
  5. Kinase activation through dimerization by human SH2-B. Nishi, M., Werner, E.D., Oh, B.C., Frantz, J.D., Dhe-Paganon, S., Hansen, L., Lee, J., Shoelson, S.E. Mol. Cell. Biol. (2005) [Pubmed]
  6. Identification of SH2B1β as a focal adhesion protein that regulates focal adhesion size and number. Lanning, N.J., Su, H.W., Argetsinger, L.S., Carter-Su, C. J. Cell. Sci. (2011) [Pubmed]
  7. Identification of SH2B2beta as an inhibitor for SH2B1- and SH2B2alpha-promoted Janus kinase-2 activation and insulin signaling. Li, M., Li, Z., Morris, D.L., Rui, L. Endocrinology (2007) [Pubmed]
  8. Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling. Rui, L., Mathews, L.S., Hotta, K., Gustafson, T.A., Carter-Su, C. Mol. Cell. Biol. (1997) [Pubmed]
  9. SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. Duan, C., Li, M., Rui, L. J. Biol. Chem. (2004) [Pubmed]
  10. SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Carter-Su, C., Rui, L., Stofega, M.R. Recent Prog. Horm. Res. (2000) [Pubmed]
  11. Interaction of fibroblast growth factor receptor 3 and the adapter protein SH2-B. A role in STAT5 activation. Kong, M., Wang, C.S., Donoghue, D.J. J. Biol. Chem. (2002) [Pubmed]
  12. SH2-B is required for both male and female reproduction. Ohtsuka, S., Takaki, S., Iseki, M., Miyoshi, K., Nakagata, N., Kataoka, Y., Yoshida, N., Takatsu, K., Yoshimura, A. Mol. Cell. Biol. (2002) [Pubmed]
  13. Lnk adaptor: novel negative regulator of B cell lymphopoiesis. Rudd, C.E. Sci. STKE (2001) [Pubmed]
  14. Association of SH2-B to phosphorylated tyrosine residues in the activation loop of TrkB. Suzuki, K., Mizutani, M., Hitomi, Y., Kizaki, T., Ohno, H., Ishida, H., Haga, S., Koizumi, S. Res. Commun. Mol. Pathol. Pharmacol. (2002) [Pubmed]
  15. Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Kurzer, J.H., Argetsinger, L.S., Zhou, Y.J., Kouadio, J.L., O'Shea, J.J., Carter-Su, C. Mol. Cell. Biol. (2004) [Pubmed]
  16. Structural basis for phosphotyrosine recognition by the Src homology-2 domains of the adapter proteins SH2-B and APS. Hu, J., Hubbard, S.R. J. Mol. Biol. (2006) [Pubmed]
  17. SH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cells. Wang, X., Chen, L., Maures, T.J., Herrington, J., Carter-Su, C. J. Biol. Chem. (2004) [Pubmed]
  18. Differential binding to and regulation of JAK2 by the SH2 domain and N-terminal region of SH2-bbeta. Rui, L., Gunter, D.R., Herrington, J., Carter-Su, C. Mol. Cell. Biol. (2000) [Pubmed]
  19. Direct interaction of nerve growth factor receptor, TrkA, with non-receptor tyrosine kinase, c-Abl, through the activation loop. Koch, A., Mancini, A., Stefan, M., Niedenthal, R., Niemann, H., Tamura, T. FEBS Lett. (2000) [Pubmed]
  20. SH2-B and APS are multimeric adapters that augment TrkA signaling. Qian, X., Ginty, D.D. Mol. Cell. Biol. (2001) [Pubmed]
  21. Structural characterization of a novel Cbl phosphotyrosine recognition motif in the APS family of adapter proteins. Hu, J., Hubbard, S.R. J. Biol. Chem. (2005) [Pubmed]
  22. Another piece in the molecular puzzle of obesity. Senior, K. Drug Discov. Today (2005) [Pubmed]
 
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