RT journal article
T1 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass
A1 Blandino-Rosano, Manuel
A1 O Scheys, Joshua
A1 Jiménez Palomares, Margarita
A1 Barbaresso, Rebecca
A1 Bender, Aaron S
A1 Yanagiya, Akiko
A1 Liu, Ming
A1 Rui, Liangyou
A1 Sonenberg, Nahum
A1 Bernal-Mizrachi, Ernesto
A2 BiomedicinaBiotecnología y Salud Pública
AB 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.
SN 1939-327X
YR 2016
FD 2016-05-23
LK http://hdl.handle.net/10498/34814
UL http://hdl.handle.net/10498/34814
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 10-nov-2026