Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway

Oncogene. 2002 Apr 4;21(15):2309-19. doi: 10.1038/sj.onc.1205297.


Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering and morphogenesis of epithelial cells through the activation of the MET tyrosine kinase receptor. Although the activated MET receptor recruits a number of signaling proteins, little is known of the downstream signaling pathways activated by HGF/SF. In this study, we wished to examine the signaling pathway leading to activation of the ETS1 transcription factor. Using in vitro and in vivo kinase assays, we found that HGF/SF activates the ERK1 MAP kinase, leading to the phosphorylation of the threonine 38 residue of ETS1 within a putative MAP kinase phosphorylation site (PLLT38P). This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF. Using kinase and transcription assays, we further demonstrated that phosphorylation and activation of ETS1 occurs downstream of a RAS-RAF-MEK-ERK pathway. The functional involvement of this pathway in HGF/SF action was demonstrated using U0126, a pharmacological inhibitor of MEK, which blocked phosphorylation and activation of ETS1, RAS-dependent transcriptional responses, cell scattering and morphogenesis. These data demonstrated that ETS1 is a downstream target of HGF/SF acting through a RAS-RAF-MEK-ERK pathway and provides a signaling pathway leading to the regulation of gene expression by HGF/SF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dogs
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Hepatocyte Growth Factor / pharmacology*
  • MAP Kinase Signaling System* / drug effects
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Morphogenesis
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*
  • Transcriptional Activation


  • Proto-Oncogene Protein c-ets-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • Phosphothreonine
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Proto-Oncogene Proteins p21(ras)