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Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming

P Peschard1, T M Fournier, L Lamorte

  • 1Department of Biochemistry, McGill University, Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada.

Molecular Cell
|December 14, 2001
PubMed

Insights

The c-Cbl protooncogene negatively regulates receptor tyrosine kinases (RTKs). Disrupting this interaction, specifically with the Met RTK, leads to deregulation and contributes to oncogenic activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The c-Cbl protooncogene acts as a negative regulator for receptor tyrosine kinases (RTKs).
  • c-Cbl mediates RTK regulation through promoting their polyubiquitination.
  • Uncoupling c-Cbl from RTKs can lead to RTK deregulation.

Purpose of the Study:

  • To investigate the mechanism by which c-Cbl regulates the Met receptor tyrosine kinase.
  • To determine if the uncoupling of c-Cbl from Met contributes to oncogenic activation.

Main Methods:

  • Investigated the interaction between c-Cbl and the Met RTK.
  • Utilized mutational analysis of Met receptor tyrosine kinase and c-Cbl.
  • Assessed ubiquitination status of Met receptor.
  • Evaluated the transforming activity of Met variants in fibroblast and epithelial cells.

Main Results:

  • Demonstrated that c-Cbl promotes the ubiquitination of the Met RTK.
  • Identified the c-Cbl tyrosine kinase binding (TKB) domain and a juxtamembrane tyrosine residue on Met as critical for this interaction.
  • Showed that a Met receptor variant lacking this juxtamembrane tyrosine is not ubiquitinated.
  • Found that this Met variant exhibits transforming activity in cellular assays.

Conclusions:

  • The interaction between c-Cbl and the Met RTK is mediated by the c-Cbl TKB domain binding to a specific juxtamembrane tyrosine residue on Met.
  • Disruption of this c-Cbl-Met interaction, as seen with the oncogenic Tpr-Met variant or by mutating the tyrosine residue, leads to Met receptor ubiquitination failure.
  • The uncoupling of c-Cbl from RTKs, including Met, represents a mechanism contributing to their oncogenic activation.

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