Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors.
Cellular Src and epidermal growth factor receptor (EGFR) collaborate in the progression of certain human malignancies, and their cooverexpression characterizes relatively aggressive animal tumors. Our study addressed the mode of oncogenic cooperation and reports that overexpression of c-Src in model cellular systems results in the accumulation of EGFR at the cell surface. The underlying mechanism involves inhibition of the normal, c-Cbl-regulated process of ligand-induced receptor down-regulation. In response to activation of c-Src, c-Cbl proteins undergo tyrosine phosphorylation that promotes their ubiquitylation and proteasomal destruction. Consequently, ubiquitylation of EGFR by c-Cbl is restrained in Src-transformed cells, and receptor sorting to endocytosis is impaired. In conclusion, by promoting destruction of c-Cbl, c-Src enables EGFR to evade desensitization, which explains Src-EGFR collaboration in oncogenesis.
Bao
Jing
J
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Gur
Gal
G
Yarden
Yosef
Y
D000818:Animals; D015152:Blotting, Northern; D016466:CHO Cells; D002461:Cell Line, Transformed; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D006133:Growth Substances; D008024:Ligands; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D019061:src-Family Kinases; C067419:CBL protein, human