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Phosphoinositide 3-kinase ? inhibits cardiac GSK-3 independently of Akt.

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

SUBMITTER: Mohan ML

PROVIDER: S-EPMC3967506 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Phosphoinositide 3-kinase γ inhibits cardiac GSK-3 independently of Akt.

Mohan Maradumane L ML Jha Babal K BK Gupta Manveen K MK Vasudevan Neelakantan T NT Martelli Elizabeth E EE Mosinski John David JD Naga Prasad Sathyamangla V SV

Science signaling 20130122 259

Activation of cardiac phosphoinositide 3-kinase α (PI3Kα) by growth factors, such as insulin, or activation of PI3Kγ 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 PI3Kγ inhibited GSK-3 independently of the insulin-PI3Kα-Akt axis. Although insulin treatment activated Akt in PI3Kγ knockout mice, phosphorylation of GSK-3 was d ...[more]

PMID: 23354687

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Project description:BACKGROUND INFORMATION:ARAP2, an Arf GTPase-activating protein (Arf GAP) that binds to adaptor protein with PH domain, PTB domain and leucine zipper motifs 1 (APPL1), regulates focal adhesions (FAs). APPL1 affects FA dynamics by regulating Akt. Here, we tested the hypothesis that ARAP2 affects FAs in part by regulating Akt through APPL1. RESULTS:We found that ARAP2 controlled FA dynamics dependent on its enzymatic Arf GAP activity. In some cells, ARAP2 also regulated phosphoAkt (pAkt) levels. However, ARAP2 control of FAs did not require Akt and conversely, the effects on pAkt were independent of FAs. Reducing ARAP2 expression reduced the size and number of FAs in U118, HeLa and MDA-MB-231 cells. Decreasing ARAP2 expression increased pAkt in U118 cells and HeLa cells and overexpressing ARAP2 decreased pAkt in U118 cells; in contrast, ARAP2 had no effect on pAkt in MDA-MB-231 cells. An Akt inhibitor did not block the effect of reduced ARAP2 on FAs in U118. Furthermore, the effect of ARAP2 on Akt did not require Arf GAP activity, which is necessary for effects on FAs and integrin traffic. Altering FAs by other means did not induce the same changes in pAkt as those seen by reducing ARAP2 in U118 cells. In addition, we discovered that ARAP2 and APPL1 had co-ordinated effects on pAkt in U118 cells. Reduced APPL1 expression, as for ARAP2, increased pAkt in U118 and the effect of reduced APPL1 expression was reversed by overexpressing ARAP2. Conversely, the effect of reduced ARAP2 expression was reversed by overexpressing APPL1. ARAP2 is an Arf GAP that has previously been reported to affect FAs by regulating Arf6 and integrin trafficking and to bind to the adaptor proteins APPL1. Here, we report that ARAP2 suppresses pAkt levels in cells co-ordinately with APPL1 and independently of GAP activity and its effect on the dynamic behaviour of FAs. CONCLUSIONS:We conclude that ARAP2 affects Akt signalling in some cells by a mechanism independent of FAs or membrane traffic. SIGNIFICANCE:Our results highlight an Arf GAP-independent function of ARAP2 in regulating Akt activity and distinguish the effect of ARAP2 on Akt from that on FAs and integrin trafficking, which requires regulation of Arf6.

Dataset Information

Phosphoinositide 3-kinase ? inhibits cardiac GSK-3 independently of Akt.

Publications

Phosphoinositide 3-kinase γ inhibits cardiac GSK-3 independently of Akt.

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