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Identification of SH2B2ß as an Inhibitor for SH2B1- and SH2B2-Promoted Janus Kinase-2 Activation and Insulin Signaling

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622

Address all correspondence and requests for reprints to: Liangyou Rui, Ph.D., Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622. E-mail: ruily{at}umich.edu.

The SH2B family has three members (SH2B1, SH2B2, and SH2B3) that contain conserved dimerization (DD), pleckstrin homology, and SH2 domains. The DD domain mediates the formation of homo- and heterodimers between members of the SH2B family. The SH2 domain of SH2B1 (previously named SH2-B) or SH2B2 (previously named APS) binds to phosphorylated tyrosines in a variety of tyrosine kinases, including Janus kinase-2 (JAK2) and the insulin receptor, thereby promoting the activation of JAK2 or the insulin receptor, respectively. JAK2 binds to various members of the cytokine receptor family, including receptors for GH and leptin, to mediate cytokine responses. In mice, SH2B1 regulates energy and glucose homeostasis by enhancing leptin and insulin sensitivity. In this work, we identify SH2B2ß as a new isoform of SH2B2 (designated as SH2B2) derived from the SH2B2 gene by alternative mRNA splicing. SH2B2ß has a DD and pleckstrin homology domain but lacks a SH2 domain. SH2B2ß bound to both SH2B1 and SH2B2, as demonstrated by both the interaction of glutathione S-transferase-SH2B2ß fusion protein with SH2B1 or SH2B2 in vitro and coimmunoprecipitation of SH2B2ß with SH2B1 or SH2B2 in intact cells. SH2B2ß markedly attenuated the ability of SH2B1 to promote JAK2 activation and subsequent tyrosine phosphorylation of insulin receptor substrate-1 by JAK2. SH2B2ß also significantly inhibited SH2B1- or SH2B2-promoted insulin signaling, including insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that SH2B2ß is an endogenous inhibitor of SH2B1 and/or SH2B2, negatively regulating insulin signaling and/or JAK2-mediated cellular responses.

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				Z. Li, Y. Zhou, C. Carter-Su, M. G. Myers Jr., and L. Rui SH2B1 Enhances Leptin Signaling by Both Janus Kinase 2 Tyr813 Phosphorylation-Dependent and -Independent Mechanisms Mol. Endocrinol., September 1, 2007; 21(9): 2270 - 2281. [Abstract] [Full Text] [PDF]