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

312 Citations (Scopus)

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

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Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
Binding Sites
Mutation
Tyrosine
Proteins
Ubiquitination
Phenylalanine
Fibroblasts
Epithelial Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. / Peschard, Pascal; Fournier, Tanya M.; Lamorte, Louie; Naujokas, Monica A.; Band, Hamid; Langdon, Wallace Y.; Park, Morag.

In: Molecular Cell, Vol. 8, No. 5, 21.11.2001, p. 995-1004.

Research output: Contribution to journalArticle

Peschard, Pascal ; Fournier, Tanya M. ; Lamorte, Louie ; Naujokas, Monica A. ; Band, Hamid ; Langdon, Wallace Y. ; Park, Morag. / Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. In: Molecular Cell. 2001 ; Vol. 8, No. 5. pp. 995-1004.
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