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

The Journal of cell biology | 2006

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

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Associated grants

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

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