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Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer

Li Ma1, Zhenbang Chen, Hediye Erdjument-Bromage

  • 1Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

Cell
|April 27, 2005
PubMed

Insights

Extracellular signal-regulated kinase (Erk) inactivates TSC2 through phosphorylation, promoting tumor growth in Tuberous Sclerosis Complex (TSC). Blocking Erk

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by tumor formation, caused by mutations in TSC1 or TSC2 genes.
  • Tumorigenesis in TSC does not always involve loss of heterozygosity (LOH).
  • Activated extracellular signal-regulated kinase (Erk) has been observed in TSC lesions without LOH.

Purpose of the Study:

  • To investigate the role of Erk in TSC tumorigenesis.
  • To elucidate the mechanism by which Erk influences TSC2 function and mTOR signaling.

Main Methods:

  • Investigating Erk-dependent phosphorylation of TSC2.
  • Analyzing TSC1-TSC2 complex dissociation.
  • Assessing the impact of TSC2 phosphorylation on mTOR signaling and cell proliferation.
  • Utilizing a non-phosphorylatable TSC2 mutant in TSC2+/- tumor cells with constitutive Erk activation.

Main Results:

  • Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation.
  • Phosphorylated TSC2 exhibits impaired inhibition of mTOR signaling, cell proliferation, and oncogenic transformation.
  • Expression of a non-phosphorylatable TSC2 mutant blocked tumor formation in vivo, whereas wild-type TSC2 did not.

Conclusions:

  • The Ras/MAPK pathway, specifically Erk, acts upstream of the TSC complex.
  • Erk modulates mTOR signaling and contributes to TSC progression via phosphorylation and inactivation of TSC2.
  • Targeting Erk may offer a therapeutic strategy for TSC.

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