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Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.

Molecular cell | Jul 1, 2002

http://www.ncbi.nlm.nih.gov/pubmed/12150915

The S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K) regulate a myriad of cellular processes. Here, we show that an approach using a combination of biochemistry and bioinformatics can identify substrates of these kinases. This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB. We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo. We also show that S939 and T1462 of tuberin are PI3K-regulated phosphorylation sites and that T1462 is constitutively phosphorylated in PTEN(-/-) tumor-derived cell lines. Finally, we find that a tuberin mutant lacking the major PI3K-dependent phosphorylation sites can block the activation of S6K1, suggesting a means by which the PI3K-Akt pathway regulates S6K1 activity.

Pubmed ID: 12150915 RIS Download

Mesh terms: 3T3 Cells | Amino Acid Sequence | Animals | Binding Sites | Cell Line | Enzyme Activation | Gene Deletion | Humans | Mice | Molecular Weight | Mutation | PTEN Phosphohydrolase | Phosphatidylinositol 3-Kinases | Phosphoric Monoester Hydrolases | Phosphorylation | Protein-Serine-Threonine Kinases | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-akt | Repressor Proteins | Ribosomal Protein S6 Kinases | Signal Transduction | Substrate Specificity | Tuberous Sclerosis | Tumor Cells, Cultured | Tumor Suppressor Proteins

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM41890
  • Agency: NIGMS NIH HHS, Id: GM51405
  • Agency: NIGMS NIH HHS, Id: GM56203
  • Agency: NIGMS NIH HHS, Id: R01 GM041890
  • Agency: NIGMS NIH HHS, Id: R01 GM056203

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