The protein product of the c-cbl oncogene rapidly complexes with the EGF receptor and is tyrosine phosphorylated following EGF stimulation.
The cbl oncogene was first identified as part of a transforming retrovirus which arose in a mouse pre-B cell lymphoma. Its protein product, p120cbl, is cytoplasmic and has several distinctive domains including a highly basic region, a RING finger motif and a large proline-rich domain. A mutation to cbl in the 70Z/3 pre-B cell lymphoma produces an oncogenic protein which exhibits a marked enhancement of tyrosine phosphorylation. Parallel studies have demonstrated that p120cbl is a substrate of protein tyrosine kinases activated by engagement of the T cell antigen receptor and that cbl is phosphorylated by oncogenic forms of the Abl tyrosine kinase. A genetic analysis of the Caenorhabditis elegans cbl homologue, sli-1, demonstrates that sli-1 negatively regulates the LET-23 tyrosine kinase receptor. Here we show that p120cbl is rapidly phosphorylated on tyrosine residues following EGF stimulation and that it forms an inducible complex with the receptor. Our results also show that the oncogenic 70Z/3 form of cbl has enhanced binding to the EGF receptor and that peptides spanning the proline-rich region bind a range SH3 domains. These findings are consistent with a conserved role for cbl/sli-1 proteins in mammals and nematodes.
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D050722:Oncogene Protein v-cbl; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D046911:Macromolecular Substances; D050722:Oncogene Protein v-cbl; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; C067419:CBL protein, human; C493849:Cbl protein, mouse