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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.

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


  • Manning BD
  • Tee AR
  • Logsdon MN
  • Blenis J
  • Cantley LC


Molecular cell

Publication Data

July 1, 2002

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

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