The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering

Mol Biol Cell. 1999 Mar;10(3):551-65. doi: 10.1091/mbc.10.3.551.

Abstract

The scatter factor/hepatocyte growth factor regulates scattering and morphogenesis of epithelial cells through activation of the MET tyrosine kinase receptor. In particular, the noncatalytic C-terminal tail of MET contains two autophosphorylation tyrosine residues, which form a multisubstrate-binding site for several cytoplasmic effectors and are thought to be essential for signal transduction. We show here that a MET receptor mutated on the four C-terminal tyrosine residues, Y1311F, Y1347F, Y1354F, and Y1363F, can induce efficiently a transcriptional response and cell scattering, whereas it cannot induce cell morphogenesis. Although the mutated receptor had lost its ability to recruit and/or activate known signaling molecules, such as GRB2, SHC, GAB1, and PI3K, by using a sensitive association-kinase assay we found that the mutated receptor can still associate and phosphorylate a approximately 250-kDa protein. By further examining signal transduction mediated by the mutated MET receptor, we established that it can transmit efficient RAS signaling and that cell scattering by the mutated MET receptor could be inhibited by a pharmacological inhibitor of the MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase) pathway. We propose that signal transduction by autophosphorylation of the C-terminal tyrosine residues is not the sole mechanism by which the activated MET receptor can transmit RAS signaling and cell scattering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Animals
  • Binding Sites
  • Cell Line
  • Cell Movement / physiology*
  • Dogs
  • GRB10 Adaptor Protein
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Transcriptional Activation
  • Transfection
  • Tyrosine / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Recombinant Proteins
  • Shc Signaling Adaptor Proteins
  • Transcription Factor AP-1
  • Transcription Factors
  • GRB10 Adaptor Protein
  • Tyrosine
  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-met
  • ras Proteins