| First Author | Blandino-Rosano M | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 8 | Pages | 2235-48 |
| PubMed ID | 27217487 | Mgi Jnum | J:246863 |
| Mgi Id | MGI:5923053 | Doi | 10.2337/db15-1443 |
| Citation | Blandino-Rosano M, et al. (2016) 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls beta-Cell Mass. Diabetes 65(8):2235-48 |
| abstractText | 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. |
