Role of Ras signaling in the induction of snail by transforming growth factor-beta

J Biol Chem. 2009 Jan 2;284(1):245-253. doi: 10.1074/jbc.M804777200. Epub 2008 Nov 14.

Abstract

The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor (TGF)-beta in some tumor cells. Here, we demonstrate the molecular mechanism whereby Snail, a key regulator of EMT, is induced by TGF-beta in tumor cells. Snail induction by TGF-beta was highly dependent on cooperation with active Ras signals, and silencing of Ras abolished Snail induction by TGF-beta in pancreatic cancer Panc-1 cells. Transfection of constitutively active Ras into HeLa cells led to induction of Snail by TGF-beta, while representative direct targets of TGF-beta, including Smad7 and PAI-1, were not affected by Ras signaling. Using mitogen-activated protein kinase inhibitors or Smad3 or Smad2 mutants, we found that phosphorylation at the linker region of Smad2/3 was not required for the induction of Snail by TGF-beta. Taken together, these findings indicate that Ras and TGF-beta-Smad signaling selectively cooperate in the induction of Snail, which occurs in a Smad-dependent manner, but independently of phosphorylation at the linker region of R-Smads by Ras signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Induction / drug effects
  • Gene Expression Regulation, Neoplastic* / drug effects
  • HeLa Cells
  • Humans
  • Mutation
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins p21(ras) / biosynthesis*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Signal Transduction* / drug effects
  • Smad Proteins / genetics
  • Smad Proteins / metabolism
  • Snail Family Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Smad Proteins
  • Snail Family Transcription Factors
  • Transcription Factors
  • Transforming Growth Factor beta
  • Proto-Oncogene Proteins p21(ras)