title: 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass.
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.
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Manuel
authors.initials: M
authors.lastname: Blandino-Rosano
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Scheys
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Margarita
authors.initials: M
authors.lastname: Jimenez-Palomares
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barbaresso
authors.affiliation: Diabetes, Obesity and Metabolism Institute, The Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Bender
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Akiko
authors.initials: A
authors.lastname: Yanagiya
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Liangyou
authors.initials: L
authors.lastname: Rui
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI VA Ann Arbor Healthcare System, Ann Arbor, MI ebernalm@med.miami.edu.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D055504:Insulin Receptor Substrate Proteins; D046912:Multiprotein Complexes; C115327:Sh2bpsm1 protein, mouse; D053614:Janus Kinase 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases