Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosis and Cancer Pathogenesis

Cell. 2005 Apr 22;121(2):179-93. doi: 10.1016/j.cell.2005.02.031.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • In Vitro Techniques
  • Kidney / cytology
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Neoplasm Transplantation
  • Neoplasms / etiology*
  • Neoplasms / metabolism*
  • Phosphorylation
  • Protein Kinases / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Serine / metabolism
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis / etiology*
  • Tuberous Sclerosis / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Repressor Proteins
  • TSC1 protein, human
  • TSC2 protein, human
  • Tsc1 protein, mouse
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Serine
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 70-kDa
  • ribosomal protein S6 kinase, 70kD, polypeptide 2
  • Extracellular Signal-Regulated MAP Kinases