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Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning.

Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.

Pubmed ID: 16636147 RIS Download

Mesh terms: Cell Line | Cell Membrane | Growth Substances | HeLa Cells | Humans | Microscopy, Confocal | Models, Biological | Phosphorylation | Proto-Oncogene Proteins c-akt | Tumor Suppressor Proteins | ras Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NICHD NIH HHS, Id: HD46282
  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: CA63613
  • Agency: NIEHS NIH HHS, Id: ES08263-06S1
  • Agency: NICHD NIH HHS, Id: R01 HD046282
  • Agency: NCI NIH HHS, Id: R01 CA063613
  • Agency: NIEHS NIH HHS, Id: R01 ES008263
  • Agency: NIEHS NIH HHS, Id: P30 ES007784
  • Agency: NIEHS NIH HHS, Id: ES07784

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Scansite searches for motifs within proteins that are likely to be phosphorylated by specific protein kinases or bind to domains such as SH2 domains, 14-3-3 domains or PDZ domains. The Motifscanner program utilizes an entropy approach that assesses the probability of a site matching the motif using the selectivity values and sums the logs of the probability values for each amino acid in the candidate sequence. The program then indicates the percentile ranking of the candidate motif in respect to all potential motifs in proteins of a protein database. When available, percentile scores of some confirmed phosphorylation sites for the kinase of interests or confirmed binding sites of the domain of interest are provided for comparison with the scores of the candidate motifs.


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