Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

摘要: Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss polarity fidelity thought occur as a consequence transformation; however, here we report that selective mistrafficking the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from basolateral apical cell surface drives transformation. Normally, EREG is preferentially delivered polarized Madin-Darby canine kidney cells. regulated by conserved tyrosine-based sorting motif in its cytoplasmic domain (YXXΦ: Y(156)ERV). Both Y156 V159 required for EREG, because Y156A V159G substitutions redirect surface. We also show adaptor protein 1B-independent. Apical has distinctive phenotype. In contrast transient EGFR tyrosine phosphorylation after stimulation, leads prolonged phosphorylation, which may be related, at least part, lack negative regulatory Y1045 subsequent ubiquitylation. Notably, cells stably expressing apically mistrafficked form significantly larger, hyperproliferative, poorly differentiated, locally invasive tumors nude mice compared with WT EREG-expressing