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 Citations (Scopus)

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

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Insulin Receptor Substrate Proteins
Carrier Proteins
Cell Survival
Eukaryotic Initiation Factor-4E
Cell Proliferation
Janus Kinase 2
Eukaryotic Initiation Factors
Biological Phenomena
Ubiquitination
Protein Biosynthesis
Cell Cycle
Homeostasis
Cytokines
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Blandino Rosano, M., Scheys, J. O., Jimenez-Palomares, M., Barbaresso, R., Bender, A. S., Yanagiya, A., ... 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

4E-BP2/SH2B1/IRS2 are part of a novel feedback loop that controls β-cell mass. / Blandino Rosano, Manuel; Scheys, Joshua O.; Jimenez-Palomares, Margarita; Barbaresso, Rebecca; Bender, Aaron S.; Yanagiya, Akiko; Liu, Ming; Rui, Liangyou; Sonenberg, Nahum; Bernal Mizrachi, Ernesto.

In: Diabetes, Vol. 65, No. 8, 01.08.2016, p. 2235-2248.

Research output: Contribution to journalArticle

Blandino Rosano, M, Scheys, JO, Jimenez-Palomares, M, Barbaresso, R, Bender, AS, 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, vol. 65, no. 8, pp. 2235-2248. https://doi.org/10.2337/db15-1443
Blandino Rosano M, Scheys JO, Jimenez-Palomares M, Barbaresso R, Bender AS, Yanagiya A et al. 4E-BP2/SH2B1/IRS2 are part of a novel feedback loop that controls β-cell mass. Diabetes. 2016 Aug 1;65(8):2235-2248. https://doi.org/10.2337/db15-1443
Blandino Rosano, Manuel ; Scheys, Joshua O. ; Jimenez-Palomares, Margarita ; Barbaresso, Rebecca ; Bender, Aaron S. ; Yanagiya, Akiko ; Liu, Ming ; Rui, Liangyou ; Sonenberg, Nahum ; Bernal Mizrachi, Ernesto. / 4E-BP2/SH2B1/IRS2 are part of a novel feedback loop that controls β-cell mass. In: Diabetes. 2016 ; Vol. 65, No. 8. pp. 2235-2248.
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