Cisplatin-induced non-canonical endocytosis of EGFR via p38 phosphorylation of the c-terminal region containing ser-1015 in non-small cell lung cancer cells

Tomohiro Tanaka, Tatsuhiko Ozawa, Eiji Oga, Atsushi Muraguchi, Hiroaki Sakurai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)9251-9256
Number of pages6
JournalOncology Letters
Volume15
Issue number6
DOIs
StatePublished - 2018/06

Keywords

  • Cisplatin
  • Endocytosis
  • Epidermal growth factor receptor
  • Non-small cell lung cancer cells
  • P38

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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