| First Author | Molinaro A | Year | 2019 |
| Journal | Cell Metab | Volume | 29 |
| Issue | 6 | Pages | 1400-1409.e5 |
| PubMed ID | 30982732 | Mgi Jnum | J:275976 |
| Mgi Id | MGI:6313678 | Doi | 10.1016/j.cmet.2019.03.010 |
| Citation | Molinaro A, et al. (2019) Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kalpha and PI3Kbeta Activities and Is Promoted by RAS. Cell Metab 29(6):1400-1409.e5 |
| abstractText | Phosphatidylinositol-3-kinase (PI3K) activity is aberrant in tumors, and PI3K inhibitors are investigated as cancer therapeutics. PI3K signaling mediates insulin action in metabolism, but the role of PI3K isoforms in insulin signaling remains unresolved. Defining the role of PI3K isoforms in insulin signaling is necessary for a mechanistic understanding of insulin action and to develop PI3K inhibitors with optimal therapeutic index. We show that insulin-driven PI3K-AKT signaling depends on redundant PI3Kalpha and PI3Kbeta activities, whereas PI3Kdelta and PI3Kgamma are largely dispensable. We have also found that RAS activity promotes AKT phosphorylation in insulin-stimulated hepatocytes and that promotion of insulin-driven AKT phosphorylation by RAS depends on PI3Kalpha. These findings reveal the detailed mechanism by which insulin activates AKT, providing an improved mechanistic understanding of insulin signaling. This improved model for insulin signaling predicts that isoform-selective PI3K inhibitors discriminating between PI3Kalpha and PI3Kbeta should be dosed below their hyperglycemic threshold to achieve isoform selectivity. |
