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Sci. Signal., 22 January 2013
Vol. 6, Issue 259, p. ra4
[DOI: 10.1126/scisignal.2003308]

RESEARCH ARTICLES

Phosphoinositide 3-Kinase {gamma} Inhibits Cardiac GSK-3 Independently of Akt

Maradumane L. Mohan1, Babal K. Jha2, Manveen K. Gupta1, Neelakantan T. Vasudevan1, Elizabeth E. Martelli1, John David Mosinski1, and Sathyamangla V. Naga Prasad1*

1 Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
2 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Abstract: Activation of cardiac phosphoinositide 3-kinase α (PI3Kα) by growth factors, such as insulin, or activation of PI3K{gamma} 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 PI3K{gamma} inhibited GSK-3 independently of the insulin-PI3Kα-Akt axis. Although insulin treatment activated Akt in PI3K{gamma} 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. PI3K{gamma} 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 PI3K{gamma} knockout mice were smaller compared to those of wild-type mice. Cardiac overexpression of a catalytically inactive PI3K{gamma} (PI3K{gamma}inact) transgene in PI3K{gamma} knockout mice reduced the activities of PPMT-1 and PP2A and increased phosphorylation of GSK-3. Furthermore, PI3K{gamma} knockout mice expressing the PI3K{gamma}inact transgene had larger hearts than wild-type or PI3K{gamma} knockout mice. Our studies show that a kinase-independent function of PI3K{gamma} could directly inhibit GSK-3 function by preventing the PP2A–PPMT-1 interaction and that this inhibition of GSK-3 was independent of Akt.

* To whom correspondence should be addressed. E-mail: prasads2{at}ccf.org

Citation: M. L. Mohan, B. K. Jha, M. K. Gupta, N. T. Vasudevan, E. E. Martelli, J. D. Mosinski, S. V. Naga Prasad, Phosphoinositide 3-Kinase {gamma} Inhibits Cardiac GSK-3 Independently of Akt. Sci. Signal. 6, ra4 (2013).

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Molecular determinants of PI3K{gamma}-mediated activation downstream of G-protein-coupled receptors (GPCRs).
O. Vadas, H. A. Dbouk, A. Shymanets, O. Perisic, J. E. Burke, W. F. Abi Saab, B. D. Khalil, C. Harteneck, A. R. Bresnick, B. Nurnberg, et al. (2013)
PNAS 110, 18862-18867
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