EGF receptor binding and transformation by v-cbl is ablated by the introduction of a loss-of-function mutation from the Caenorhabditis elegans sli-1 gene.
The 120 kD product of the c-cbl oncogene is rapidly tyrosine phosphorylated and recruited to the EGF receptor following ligand binding. Cbl's oncogenic potential is activated by a large carboxy-terminal truncation that generated v-cbl and removes the Ring finger and proline-rich SH3-binding domains. Here we show that this truncation reveals a novel and highly conserved domain that can interact directly with the EGF receptor in a phosphorylation dependent manner. Furthermore we demonstrate that the v-cbl domain is not utilized by c-cbl for recruitment to the receptor since this binding property is not evident in c-cbl constructs with proline domain deletions, and it is only revealed following deletion of the Ring finger. We also analyse a loss-of-function mutation from the C. elegans homologue, sli-1, and show that the corresponding mutation in v-cbl ablates transformation and EGF receptor association. Thus our findings provide further evidence that v-cbl possesses a novel and evolutionarily conserved phosphotyrosine binding domain and that the dual capability of EGF receptor binding by cbl involves two distinct mechanisms. In addition these findings raise the possibility that v-cbl may transform by competing with c-cbl for phosphorylated binding sites on activated receptor complexes.
Thien
C B
CB
Department of Pathology, The University of Western Australia, Queen Elizabeth II Medical Centre, Nedlands.
Langdon
W Y
WY
D016475:3T3 Cells / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D017124:Conserved Sequence; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D015801:Helminth Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D050722:Oncogene Protein v-cbl; D010766:Phosphorylation / Q000187:drug effects; D011392:Proline / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011817:Rabbits; D015682:Retroviridae Proteins, Oncogenic / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D050722:Oncogene Protein v-cbl; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; C095237:Sli-1 protein, C elegans; D014443:Tyrosine; D004815:Epidermal Growth Factor; D011392:Proline; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C493849:Cbl protein, mouse