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


Editor's Summary

Making a Bigger Heart
Pathological cardiac hypertrophy can be fatal because it can cause congestive heart failure and arrhythmias. Glycogen synthase kinase-3 (GSK-3), which inhibits cardiac hypertrophy, is active when dephosphorylated by the protein phosphatase PP2A, the activity of which is stimulated by methylation mediated by the methyltransferase PPMT-1. Mohan et al. found that mice lacking the {gamma} isoform of phosphoinositide 3-kinase (PI3K) had smaller hearts than wild-type mice and showed decreased phosphorylation of GSK-3. In addition, these mice showed increased activity of PP2A and PPMT-1. Biochemical experiments indicated that PI3K{gamma} inhibited the interaction between PP2A and PPMT-1. Heart size and phosphorylation of GSK-3 were increased, and the association of PP2A with PPMT-1 was decreased in PI3K{gamma} knockout mice by expression of a catalytically inactive form of PI3K{gamma}. Thus, PI3K{gamma} promotes cardiac hypertrophy by attenuating the PP2A–PPMT-1 interaction and the inactivation of GSK-3 in a kinase-independent manner.

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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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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