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TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth

Ken Inoki1, Hongjiao Ouyang, Tianqing Zhu

  • 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Cell
|September 9, 2006
PubMed

Insights

Wnt signaling activates the mTOR pathway by inhibiting GSK3, promoting cell growth and tumor development. Rapamycin can block this Wnt-induced growth, offering potential cancer therapy.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Tuberous sclerosis complex arises from TSC2 tumor suppressor mutations, impacting cell growth regulation.
  • TSC2 normally inhibits cell growth by activating Rheb GTPase, suppressing mTOR signaling.
  • mTOR (mechanistic Target of Rapamycin) is a key regulator of cell growth and proliferation.

Purpose of the Study:

  • To elucidate the mechanism by which Wnt signaling activates mTOR.
  • To investigate the role of GSK3 and AMPK in Wnt-mediated mTOR activation.
  • To assess the therapeutic potential of mTOR inhibition in Wnt-driven cancers.

Main Methods:

  • Investigated Wnt signaling effects on the TSC2-Rheb-mTOR pathway.
  • Utilized phosphorylation site analysis to understand GSK3 and AMPK roles.
  • Tested rapamycin's efficacy in blocking Wnt-induced cell growth and tumor formation in preclinical models.

Main Results:

  • Wnt activates mTOR by inhibiting GSK3, independently of beta-catenin transcription.
  • GSK3 phosphorylates TSC2, a process primed by AMPK, thereby inhibiting mTOR.
  • Rapamycin treatment effectively blocked Wnt-induced cell proliferation and tumor growth.

Conclusions:

  • Wnt signaling stimulates cell growth and translation via the TSC-mTOR pathway, beyond transcriptional effects.
  • Sequential phosphorylation of TSC2 by AMPK and GSK3 integrates signals for cell growth control.
  • Targeting mTOR with rapamycin presents a viable therapeutic strategy for cancers with active Wnt signaling.

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