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

Pascal Peschard, Tanya M. Fournier, Louie Lamorte, Monica A. Naujokas, Hamid Band, Wallace Y. Langdon, Morag Park

Research output: Contribution to journalArticle

320 Scopus citations

Abstract

The c-Cbl protooncogene is a negative regulator for several receptor tyrosine kinases (RTKs) through its ability to promote their polyubiquitination. Hence, uncoupling c-Cbl from RTKs may lead to their deregulation. In testing this, we show that c-Cbl promotes ubiquitination of the Met RTK. This requires the c-Cbl tyrosine kinase binding (TKB) domain and a juxtamembrane tyrosine residue on Met. This tyrosine provides a direct binding site for the c-Cbl TKB domain, and is absent in the rearranged oncogenic Tpr-Met variant. A Met receptor, where the juxtamembrane tyrosine is replaced by phenylalanine, is not ubiquitinated and has transforming activity in fibroblast and epithelial cells. We propose the uncoupling of c-Cbl from RTKs as a mechanism contributing to their oncogenic activation.

Original languageEnglish (US)
Pages (from-to)995-1004
Number of pages10
JournalMolecular Cell
Volume8
Issue number5
DOIs
StatePublished - Nov 21 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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