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

Cell | Apr 22, 2005

http://www.ncbi.nlm.nih.gov/pubmed/15851026

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 RIS Download

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

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Associated grants

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

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