Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis

Nat Commun. 2012;3:1168. doi: 10.1038/ncomms2173.

Abstract

Mammalian cells contain three closely related ras genes, H-ras, K-ras and N-ras. Although in a given tumour type, oncogenic mutations are selectively observed in only one of the ras genes, the acquisition of the transformed phenotype has been shown to require the contribution of the normal products of the other ras genes. Here we demonstrate that oncogenic K-Ras promotes the activation of wild-type H- and N-Ras. This activation is mediated by oncogenic K-Ras-dependent allosteric stimulation of Sos and confers a growth advantage to oncogenic K-Ras harbouring cancer cells. These findings underscore the complementary functions of oncogenic and wild-type Ras in tumour cells and identify a potential new targeting strategy for Ras-driven tumours.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Genes, ras / genetics*
  • Humans
  • Mice
  • Mice, Nude
  • Protein Isoforms / metabolism
  • Signal Transduction
  • Son of Sevenless Protein, Drosophila / metabolism*
  • Xenograft Model Antitumor Assays
  • ras Proteins / metabolism*

Substances

  • Protein Isoforms
  • Son of Sevenless Protein, Drosophila
  • ras Proteins