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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Cell Transformation, Neoplastic / genetics
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Fibroblasts / physiology
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Humans
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Immunoblotting
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Mice
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Models, Biological
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Phosphorylation
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-met / genetics
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Proto-Oncogene Proteins c-met / metabolism*
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Rats
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Recombinant Fusion Proteins / metabolism
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases*
Substances
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Ubiquitin
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Proto-Oncogene Proteins c-met
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CBL protein, human
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Cbl protein, mouse