title: Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin.
abstract: 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.
authors.affiliation: 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.
authors.forename: Han C
authors.initials: HC
authors.lastname: Dan
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Richard I
authors.initials: RI
authors.lastname: Feldman
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Sui
authors.forename: Chien Chen
authors.initials: CC
authors.lastname: Ou
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Yeung
authors.forename: Dicky J J
authors.initials: DJ
authors.lastname: Halley
authors.forename: Santo V
authors.initials: SV
authors.lastname: Nicosia
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Pledger
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001769:Blood; D002460:Cell Line; D016147:Genes, Tumor Suppressor; D006801:Humans; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624652:Tsc1 protein, rat; C000624655:Tsc2 protein, rat; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494920:Akt1 protein, rat; C494923:Akt2 protein, rat