Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein.
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.
Peschard
P
P
Department of Biochemistry, McGill University, Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada.
Fournier
T M
TM
Lamorte
L
L
Naujokas
M A
MA
Band
H
H
Langdon
W Y
WY
Park
M
M
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019859:Proto-Oncogene Proteins c-met; C067419:CBL protein, human; C493849:Cbl protein, mouse