Research ArticlePhysiology

Phosphoinositide 3-Kinase γ Inhibits Cardiac GSK-3 Independently of Akt

Sci. Signal.  22 Jan 2013:
Vol. 6, Issue 259, pp. ra4
DOI: 10.1126/scisignal.2003308

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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 γ 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 PI3Kγ 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 PI3Kγ knockout mice by expression of a catalytically inactive form of PI3Kγ. Thus, PI3Kγ promotes cardiac hypertrophy by attenuating the PP2A–PPMT-1 interaction and the inactivation of GSK-3 in a kinase-independent manner.