4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass

• DOI: 10.2337/db15-1443
• Publication Date: 2016-05-24T04:59:07Z
• Authors: Manuel Blandino-R...; Joshua O. Scheys; Margarita Jimenez...; Rebecca Barbaresso; Aaron S. Bender; Akiko Yanagiya; Ming Liu; Liangyou Rui; Nahum Sonenberg; Ernesto Bernal-Mi...
• Keywords: Male; 0301 basic medicine; Cell Survival; Protein Stability; TOR Serine-Threonine Kinases; Cell Cycle; Janus Kinase 2; Mechanistic Target of Rapamycin Complex 1; Biochemistry; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cell Line, Tumor; Insulin-Secreting Cells; Multiprotein Complexes; Insulin Receptor Substrate Proteins; Animals; Eukaryotic Initiation Factors; Adaptor Proteins, Signal Transducing; Cell Proliferation; Signal Transduction

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.