. . . . . . . . . . . "38" . "2002-9-16" . "Normal cellular functions of hamartin and tuberin, encoded by the TSC1 and TSC2 tumor suppressor genes, are closely related to their direct interactions. However, the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented. Here we show that insulin or insulin growth factor (IGF) 1 stimulates phosphorylation of tuberin, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059. Expression of constitutively active PI3K or active Akt, including Akt1 and Akt2, induces tuberin phosphorylation. We further demonstrate that Akt/PKB associates with hamartin-tuberin complexes, promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes. The ability to form complexes, however, is not blocked. Akt also inhibits tuberin-mediated degradation of p27(kip1), thereby promoting CDK2 activity and cellular proliferation. Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K/Akt is a major mechanism controlling hamartin-tuberin function." . . . "eng" . . "IM" . . . . . . . . . . . . . . . . "MEDLINE" . "Sep" . "0021-9258" . . . . . . . . . . . . . "Print" . "20" . "277" . "NLM" . "Y" . "35364-70" . "2011-11-17" . . . . . . . . . . . . . . . . . . . . "2002" . "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin." . "Department of Pathology, Molecular Oncology, and Drug Discovery Programs, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA." . "Journal Article" . "Research Support, U.S. Gov't, P.H.S." . "Research Support, U.S. Gov't, Non-P.H.S." .