Identification of SH2B2β as an Inhibitor for SH2B1- and SH2B2α-Promoted Janus Kinase-2 Activation and Insulin Signaling
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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 SH2B2β as a new isoform of SH2B2 (designated as SH2B2α) derived from the SH2B2 gene by alternative mRNA splicing. SH2B2β has a DD and pleckstrin homology domain but lacks a SH2 domain. SH2B2β bound to both SH2B1 and SH2B2α, as demonstrated by both the interaction of glutathione S-transferase-SH2B2β fusion protein with SH2B1 or SH2B2α in vitro and coimmunoprecipitation of SH2B2β with SH2B1 or SH2B2α in intact cells. SH2B2β markedly attenuated the ability of SH2B1 to promote JAK2 activation and subsequent tyrosine phosphorylation of insulin receptor substrate-1 by JAK2. SH2B2β also significantly inhibited SH2B1- or SH2B2α-promoted insulin signaling, including insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that SH2B2β is an endogenous inhibitor of SH2B1 and/or SH2B2α, negatively regulating insulin signaling and/or JAK2-mediated cellular responses.
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SH2B1 appears to facilitate Jak2-mediated IRS phosphorylation in response to leptin receptor activation.
“A potential mechanism linking the leptin receptor to IRS-PI3K signaling involves the protein SH2B1 (103), which appears to facilitate Jak2-mediated IRS phosphorylation in response to leptin receptor activation.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [103]
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Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
- Authors
- Li, M., Li, Z., Morris, D. L., & Rui, L.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Rui, Liangyou
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2007-04-01
- Volume
- 148
- Issue
- 4
- Pages
- 1615-1621
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC4710543
- OpenAlex
- W2068550248
- Cited by
- 39
- References
- 38
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 3 · 2012: 7
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- University of Michigan (P30 CA46592, 48109, 5 P30 CA46592)
- National Institutes of Health (5P60 DK20572, CA46592, DK20572)
- College of Pharmacy, University of Michigan
- Medical School, University of Michigan
- National Cancer Institute (5P30 CA 46592, P30CA046592)
- National Institute of Diabetes and Digestive and Kidney Diseases (5P60DK-20572, P60DK020572, R01DK073601, R01DK065122)
- National Institute of Neurological Disorders and Stroke (F31NS056575)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- SH2B1, alternative mRNA splicing, insulin signaling, IRS-1, SH2 domain, dimerization domain, pleckstrin homology domain, insulin receptor, leptin sensitivity, glucose homeostasis, negative regulation of signaling
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cells, Cultured, Humans, Insulin, Male, Molecular Sequence Data, Phosphoproteins, Protein Binding, Signal Transduction, Mice, Knockout, Protein Isoforms, Adaptor Proteins, Vesicular Transport, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Janus Kinase 2
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