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

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

doi:10.3892/ol.2018.8485

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

Authors:
- Tomohiro Tanaka
- Tatsuhiko Ozawa
- Eiji Oga
- Atsushi Muraguchi
- Hiroaki Sakurai
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Affiliations: Department of Cancer Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan, Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930‑0194, Japan
Published online on: April 13, 2018 https://doi.org/10.3892/ol.2018.8485
Pages: 9251-9256

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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.

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