Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR

J Clin Invest. 2003 Oct;112(8):1223-33. doi: 10.1172/JCI17222.

Abstract

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cellular Senescence
  • Down-Regulation
  • Male
  • Mice
  • Phosphatidylinositol 3-Kinases / physiology*
  • Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases*
  • Proteins / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Platelet-Derived Growth Factor / analysis*
  • Repressor Proteins / physiology*
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Proteins

Substances

  • Proteins
  • Proto-Oncogene Proteins
  • 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 Protein p53
  • Tumor Suppressor Proteins
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Receptors, Platelet-Derived Growth Factor
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases