| First Author | Kearney AL | Year | 2019 |
| Journal | J Biol Chem | Volume | 294 |
| Issue | 45 | Pages | 16729-16739 |
| PubMed ID | 31548312 | Mgi Jnum | J:282915 |
| Mgi Id | MGI:6383528 | Doi | 10.1074/jbc.RA119.010036 |
| Citation | Kearney AL, et al. (2019) Serine 474 phosphorylation is essential for maximal Akt2 kinase activity in adipocytes. J Biol Chem 294(45):16729-16739 |
| abstractText | The Ser/Thr protein kinase Akt regulates essential biological processes such as cell survival, growth, and metabolism. Upon growth factor stimulation, Akt is phosphorylated at Ser(474); however, how this phosphorylation contributes to Akt activation remains controversial. Previous studies, which induced loss of Ser(474) phosphorylation by ablating its upstream kinase mTORC2, have implicated Ser(474) phosphorylation as a driver of Akt substrate specificity. Here we directly studied the role of Akt2 Ser(474) phosphorylation in 3T3-L1 adipocytes by preventing Ser(474) phosphorylation without perturbing mTORC2 activity. This was achieved by utilizing a chemical genetics approach, where ectopically expressed S474A Akt2 was engineered with a W80A mutation to confer resistance to the Akt inhibitor MK2206, and thus allow its activation independent of endogenous Akt. We found that insulin-stimulated phosphorylation of four bona fide Akt substrates (TSC2, PRAS40, FOXO1/3a, and AS160) was reduced by approximately 50% in the absence of Ser(474) phosphorylation. Accordingly, insulin-stimulated mTORC1 activation, protein synthesis, FOXO nuclear exclusion, GLUT4 translocation, and glucose uptake were attenuated upon loss of Ser(474) phosphorylation. We propose a model where Ser(474) phosphorylation is required for maximal Akt2 kinase activity in adipocytes. |
