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

Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Importantly, expression of an Erk nonphosphorylatable TSC2 mutant in TSC2+/- tumor cells where Erk is constitutively activated blocks tumorigenecity in vivo, while wild-type TSC2 is ineffective. Our findings position the Ras/MAPK pathway upstream of the TSC complex and suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2.

Pubmed ID: 15851026

Authors

  • Ma L
  • Chen Z
  • Erdjument-Bromage H
  • Tempst P
  • Pandolfi PP

Journal

Cell

Publication Data

April 22, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: P30 CA08748
  • Agency: NCI NIH HHS, Id: U01 CA-84292

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Extracellular Signal-Regulated MAP Kinases
  • Humans
  • In Vitro Techniques
  • Kidney
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Neoplasms
  • Phosphorylation
  • Protein Kinases
  • Repressor Proteins
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Serine
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis
  • Tumor Suppressor Proteins