Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.
Journal:
Mol. Cell 2002 JulAuthors:
Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC
Abstract
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, A
...[more]kt/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.[less]
Mesh Headings:
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