4E-BP2/SH2B1/IRS2 are part of a novel feedback loop that controls β-cell mass

Manuel Blandino-Rosano, Joshua O. Scheys, Margarita Jimenez-Palomares, Rebecca Barbaresso, Aaron S. Bender, Akiko Yanagiya, Ming Liu, Liangyou Rui, Nahum Sonenberg, Ernesto Bernal-Mizrachi

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and β-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and β-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of β-cells.

Original languageEnglish (US)
Pages (from-to)2235-2248
Number of pages14
JournalDiabetes
Volume65
Issue number8
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Blandino-Rosano, M., Scheys, J. O., Jimenez-Palomares, M., Barbaresso, R., Bender, A. S., Yanagiya, A., Liu, M., Rui, L., Sonenberg, N., & Bernal-Mizrachi, E. (2016). 4E-BP2/SH2B1/IRS2 are part of a novel feedback loop that controls β-cell mass. Diabetes, 65(8), 2235-2248. https://doi.org/10.2337/db15-1443