Mol Cell. 2001 Nov;8(5):995-1004.

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

Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M.

Source

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

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.

PMID:: 11741535; [PubMed - indexed for MEDLINE]

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