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Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin.

http://www.ncbi.nlm.nih.gov/pubmed/12167664

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.

Pubmed ID: 12167664 RIS Download

Mesh terms: Amino Acid Sequence | Animals | Blood | Cell Line | Genes, Tumor Suppressor | Humans | Hydrolysis | Insulin | Insulin-Like Growth Factor I | Phosphatidylinositol 3-Kinases | Phosphorylation | Protein-Serine-Threonine Kinases | Proteins | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-akt | Rats | Repressor Proteins | Substrate Specificity | Tumor Suppressor Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: CA77935
  • Agency: NCI NIH HHS, Id: CA89242

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