Abl tyrosine kinase regulates endocytosis of the epidermal growth factor receptor.
Signal attenuation from ligand-activated epidermal growth factor receptor (EGFR) is mediated in part by receptor endocytosis and trafficking to the lysosomal degradative compartment. Uncoupling the activated EGFR from endocytosis and degradation has emerged as a mechanism for oncogenic activation of the EGFR. The Abl nonreceptor tyrosine kinase is activated by ligand-stimulated EGFR, but the role of Abl in EGFR signaling has not been defined. Here we uncovered a novel role for the activated Abl kinase in the regulation of EGFR endocytosis. We show that activated Abl impairs EGFR internalization. Moreover, we show that activated Abl phosphorylates the EGFR primarily on tyrosine 1173, and that mutation of this site to phenylalanine restores ligand-dependent endocytosis of the EGFR in the presence of activated Abl. Furthermore, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent down-regulation by inhibiting the accumulation of Cbl at the plasma membrane in response to epidermal growth factor stimulation and disrupting the formation of the EGFR.Cbl complex without affecting Cbl protein stability. These findings reveal a novel role for Abl in promoting increased cell-surface expression of the EGFR and suggest that Abl/EGFR signaling may cooperate in human tumors.
Tanos
Barbara
B
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Pendergast
Ann Marie
AM
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D016895:Culture Media, Serum-Free; D004705:Endocytosis; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005456:Fluorescent Dyes; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D010649:Phenylalanine / Q000378:metabolism; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000037:antagonists & inhibitors; D012235:Rhodamines; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D016895:Culture Media, Serum-Free; D005456:Fluorescent Dyes; D008024:Ligands; D012235:Rhodamines; D014443:Tyrosine; D010649:Phenylalanine; D004815:Epidermal Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; D066246:ErbB Receptors; D016315:Proto-Oncogene Proteins c-abl