| First Author | Mohan ML | Year | 2013 |
| Journal | Sci Signal | Volume | 6 |
| Issue | 259 | Pages | ra4 |
| PubMed ID | 23354687 | Mgi Jnum | J:260219 |
| Mgi Id | MGI:6142530 | Doi | 10.1126/scisignal.2003308 |
| Citation | Mohan ML, et al. (2013) Phosphoinositide 3-kinase gamma inhibits cardiac GSK-3 independently of Akt. Sci Signal 6(259):ra4 |
| abstractText | Activation of cardiac phosphoinositide 3-kinase alpha (PI3Kalpha) by growth factors, such as insulin, or activation of PI3Kgamma downstream of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors stimulates the activity of the kinase Akt, which phosphorylates and inhibits glycogen synthase kinase-3 (GSK-3). We found that PI3Kgamma inhibited GSK-3 independently of the insulin-PI3Kalpha-Akt axis. Although insulin treatment activated Akt in PI3Kgamma knockout mice, phosphorylation of GSK-3 was decreased compared to control mice. GSK-3 is activated when dephosphorylated by the protein phosphatase 2A (PP2A), which is activated when methylated by the PP2A methyltransferase PPMT-1. PI3Kgamma knockout mice showed increased activity of PPMT-1 and PP2A and enhanced nuclear export of the GSK-3 substrate NFATc3. GSK-3 inhibits cardiac hypertrophy, and the hearts of PI3Kgamma knockout mice were smaller compared to those of wild-type mice. Cardiac overexpression of a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) transgene in PI3Kgamma knockout mice reduced the activities of PPMT-1 and PP2A and increased phosphorylation of GSK-3. Furthermore, PI3Kgamma knockout mice expressing the PI3Kgamma(inact) transgene had larger hearts than wild-type or PI3Kgamma knockout mice. Our studies show that a kinase-independent function of PI3Kgamma could directly inhibit GSK-3 function by preventing the PP2A-PPMT-1 interaction and that this inhibition of GSK-3 was independent of Akt. |
