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

Sheng-Li Cai1, Andrew R Tee, John D Short

  • 1Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, 78957, USA.

The Journal of Cell Biology
|April 26, 2006
PubMed

Insights

Loss of tuberin (TSC2) function activates mTOR signaling, promoting tumor growth. Growth factors trigger AKT-mediated tuberin phosphorylation, causing its cytosolic translocation and relieving mTOR inhibition by sequestering it from Rheb.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of tumor suppression
  • Mammalian target of rapamycin (mTOR) pathway

Background:

  • Loss of tuberin (TSC2) function elevates mammalian target of rapamycin (mTOR) signaling, driving cell proliferation and tumor formation.
  • The precise mechanisms by which tuberin normally represses mTOR signaling and how this repression is relieved upon growth factor stimulation remain unclear.
  • The role of hamartin in regulating tuberin's function and mTOR signaling is not fully understood.

Purpose of the Study:

  • To elucidate how tuberin normally represses mTOR signaling in the presence of growth factors.
  • To investigate the role of hamartin in the tuberin-mediated regulation of mTOR signaling.
  • To understand the molecular events leading to the activation of mTOR signaling in response to growth factors.

Main Methods:

  • Immunofluorescence and co-localization studies to determine protein localization.
  • Analysis of tuberin phosphorylation and its effect on GTPase-activating protein (GAP) activity.
  • Investigating the interaction of tuberin with 14-3-3 proteins and Rheb.

Main Results:

  • Hamartin and hypophosphorylated tuberin co-localize at the cell membrane, where tuberin inhibits Rheb signaling via its GAP activity.
  • Growth factor stimulation induces AKT-mediated phosphorylation of tuberin at specific serine residues (939 and 981).
  • Phosphorylated tuberin translocates to the cytosol, binds to 14-3-3 proteins, and is sequestered away from membrane-bound hamartin and Rheb, thereby relieving mTOR repression.

Conclusions:

  • Tuberin's membrane localization, facilitated by hamartin, is crucial for its inhibitory function on Rheb and mTOR signaling.
  • AKT-mediated phosphorylation of tuberin serves as a key switch, promoting its cytosolic sequestration and the subsequent activation of mTOR signaling.
  • This mechanism highlights how growth signals overcome tuberin's tumor-suppressive activity, offering insights into cancer development and potential therapeutic strategies.

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