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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


  • Cai SL
  • Tee AR
  • Short JD
  • Bergeron JM
  • Kim J
  • Shen J
  • Guo R
  • Johnson CL
  • Kiguchi K
  • Walker CL


The Journal of cell biology

Publication Data

April 24, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA16672
  • Agency: NCI NIH HHS, Id: CA63613
  • Agency: NIEHS NIH HHS, Id: ES07784
  • Agency: NIEHS NIH HHS, Id: ES08263-06S1
  • Agency: NICHD NIH HHS, Id: HD46282

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