Epidermal growth factor receptor (EGFR), one of the most characterized receptor tyrosine kinases (RTKs), regulates many cellular functions, including survival, proliferation, and differentiation. The aberrant activation of EGFR by overexpression or activating mutations is a major mechanism underlying the pathogenesis of human cancers, including colorectal and lung cancers, and participates in acquired resistance to anti-cancer agents (1-4).Ligand-bound EGFR proteins form an asymmetric homodimer on the plasma membrane, which is followed by the activation of its tyrosine kinase. Activated EGFR is then rapidly internalized via clathrin-mediated endocytosis and clathrin-independent endocytosis. Sequential sorting to several vesicular transport systems, including early endosomes, late endosomes, multivesicular bodies (MVBs), and recycling endosomes, http://www.jbc.org/cgi

Abstract. The aberrant activation of receptor tyrosine kinases (RTKs) is associated with tumor initiation in various types of human cancer, including non-small cell lung cancers (NSCLCs). Tyrosine kinase-independent non-canonical RTK regulation has also been investigated in tumor malignant alterations, including cellular stress responses. It was recently reported that the phosphorylation of epidermal growth factor receptor (EGFR) at C-terminal Ser-1015 serves a critical role in growth factor and cytokine signaling. In the present study, the role of non-canonical EGFR regulation has been investigated in NSCLC cells treated with cisplatin, a common chemotherapeutic agent. Cisplatin-induced p38 activation triggered the Ser-1015 phosphorylation of EGFR, with similar kinetics to previously reported Ser-1047 phosphorylation, in a tyrosine kinase-independent manner. In addition, phosphorylation around Ser-1015 triggered endocytosis of a dimer deficient mutant of EGFR. The non-canonical endocytosis of EGFR monomers was primarily controlled by the region around Ser-1015 only; however, Ser-1047 on internalized EGFR was equally phosphorylated. The results of the present study provide mechanistic evidence for the cisplatin-induced non-canonical regulation of EGFR.