ABL TYROSINE KINASE REGULATES ENDOCYTOSIS OF THE EPIDERMAL GROWTH FACTOR RECEPTOR

Abstract

Signal attenuation from ligand-activated epidermal growth factor receptor (EGFR)is mediated in part by receptor endocytosis and targeting to the lysosomal degradative compartment. Uncoupling the activated EGFR from endocytosis and degradation has emerged as a mechanism for oncogenic activation of the EGFR. A poorly characterized downstream target of the EGFR is the Abl nonreceptor tyrosine kinase. Here we uncover 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. Further, we show that activated Abl allows the ligand-activated EGFR to escape Cbl-dependent downregulation by inhibiting the accumulation of Cbl to the plasma membrane in response to EGF stimulation and disrupting the formation of an 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.