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Sci. Signal., 19 July 2011
Vol. 4, Issue 182, p. ra46
[DOI: 10.1126/scisignal.2001465]

RESEARCH ARTICLES

The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy

Nagalingam R. Sundaresan1, Vinodkumar B. Pillai1, Don Wolfgeher2, Sadhana Samant1, Prabhakaran Vasudevan3, Vishwas Parekh3, Hariharasundaram Raghuraman4, John M. Cunningham3, Madhu Gupta5, and Mahesh P. Gupta1*

1 Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
2 Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
3 Department of Pediatrics, Committee on Developmental Biology, University of Chicago, Chicago, IL 60637, USA.
4 Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
5 Department of Physiology and Biophysics, University of Illinois, Chicago, IL 60607, USA.

Abstract: Signaling through the kinase Akt regulates many biological functions. Akt is activated during growth factor stimulation through a process that requires binding of Akt to phosphatidylinositol 3,4,5-trisphosphate (PIP3), which promotes membrane localization and phosphorylation of Akt by the upstream kinase PDK1 (phosphoinositide-dependent protein kinase 1). We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP3 binding. Acetylation blocked binding of Akt and PDK1 to PIP3, thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP3 and promoted their activation. Mice injected with cells expressing a mutant that mimicked a constitutively acetylated form of Akt developed smaller tumors than those injected with cells expressing wild-type Akt. Furthermore, impaired Akt activation in the hearts of SIRT1-deficient mice was associated with reduced cardiac hypertrophy in response to physical exercise and angiotensin II. These findings uncover a key posttranslational modification of Akt that is important for its oncogenic and hypertrophic activities.

* To whom correspondence should be addressed. E-mail: mgupta{at}surgery.bsd.uchicago.edu

Citation: N. R. Sundaresan, V. B. Pillai, D. Wolfgeher, S. Samant, P. Vasudevan, V. Parekh, H. Raghuraman, J. M. Cunningham, M. Gupta, M. P. Gupta, The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy. Sci. Signal. 4, ra46 (2011).

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