Antisense repression of proto-oncogene c-Cbl enhances activation of the JAK-STAT pathway but not the ras pathway in epidermal growth factor receptor signaling.
Many growth factors including epidermal growth factor (EGF) induce tyrosine phosphorylation of the c-Cbl proto-oncogene product, whose function, however, remains unclear. Recently, Sli-1, a Caenorhabditis elegans homologue of c-Cbl, was found to be a negative regulator of let-23-mediated vulval induction pathway, suggesting that c-Cbl may negatively regulate EGF receptor (EGFR)-mediated signaling. In this study, by an antisense RNA approach, we examined the effects of expression level of c-Cbl on EGFR signaling and showed that overexpression of c-Cbl reduces and antisense repression of c-Cbl enhances autophosphorylation of EGF receptors and activation of the JAK-STAT pathway. However, in contrast to the Sli-1 protein, the expressed amount of c-Cbl does not affect activation of the Ras pathway, suggesting that the EGFR-mediated signaling pathways are differently regulated by c-Cbl among nematodes and mammals.
Ueno
H
H
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Sasaki
K
K
Miyagawa
K
K
Honda
H
H
Mitani
K
K
Yazaki
Y
Y
Hirai
H
H
D016475:3T3 Cells; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000502:physiology*; D015801:Helminth Proteins / Q000378:metabolism; D051379:Mice; D016297:Mutagenesis, Site-Directed; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D018631:ras Proteins / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; C095237:Sli-1 protein, C elegans; D015534:Trans-Activators; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D018631:ras Proteins; C493849:Cbl protein, mouse