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

Mol Cell. 2001 Nov;8(5):995-1004. doi: 10.1016/s1097-2765(01)00378-1.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Fibroblasts / physiology
  • Humans
  • Immunoblotting
  • Mice
  • Models, Biological
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism*
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases*


  • Proto-Oncogene Proteins
  • Recombinant Fusion Proteins
  • Ubiquitin
  • Proto-Oncogene Proteins c-cbl
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-met
  • CBL protein, human
  • Cbl protein, mouse