title: The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy.
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 (PIP(3)), 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 PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) 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.
authors.affiliation: Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
authors.forename: Nagalingam R
authors.initials: NR
authors.lastname: Sundaresan
authors.forename: Vinodkumar B
authors.initials: VB
authors.lastname: Pillai
authors.forename: Don
authors.initials: D
authors.lastname: Wolfgeher
authors.forename: Sadhana
authors.initials: S
authors.lastname: Samant
authors.forename: Prabhakaran
authors.initials: P
authors.lastname: Vasudevan
authors.forename: Vishwas
authors.initials: V
authors.lastname: Parekh
authors.forename: Hariharasundaram
authors.initials: H
authors.lastname: Raghuraman
authors.forename: John M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Madhu
authors.initials: M
authors.lastname: Gupta
authors.forename: Mahesh P
authors.initials: MP
authors.lastname: Gupta
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D018129:Phosphatidylinositol Phosphates / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1