@misc{10498/34814,
year = {2016},
month = {5},
url = {http://hdl.handle.net/10498/34814},
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 beta-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 beta-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 beta-cells.},
title = {4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass},
doi = {10.2337/db15-1443},
author = {Blandino-Rosano, Manuel and O Scheys, Joshua and Jiménez Palomares, Margarita and Barbaresso, Rebecca and Bender, Aaron S and Yanagiya, Akiko and Liu, Ming and Rui, Liangyou and Sonenberg, Nahum and Bernal-Mizrachi, Ernesto},
}