EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation

• Published in: Cellular signalling 2016-08, Vol.28 (8), p.937-945
• Main Authors: Hamaoka, Yuho, Negishi, Manabu, Katoh, Hironori
• Format: Article
• Language: English
• Subjects: Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Bromodeoxyuridine - metabolism; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; EGF; EphA2; Epidermal Growth Factor - pharmacology; Glioblastoma; Glioblastoma - enzymology; Glioblastoma - pathology; Humans; MAP Kinase Signaling System - drug effects; Phosphorylation - drug effects; Phosphoserine - metabolism; Receptor, EphA2 - metabolism; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RSK; Signal Transduction - drug effects
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2016.04.009

EphA2, a member of the Eph receptor tyrosine kinases, is frequently overexpressed in a variety of malignancies, including glioblastoma, and its expression is correlated with poor prognosis. EphA2 acts as a tumor promoter through a ligand ephrin-independent mechanism, which requires phosphorylation of EphA2 on serine 897 (S897), leading to increased cell migration and invasion. In this study, we show that ligand-independent EphA2 signaling occurs downstream of the MEK/ERK/RSK pathway and mediates epidermal growth factor (EGF)-induced cell proliferation in glioblastoma cells. Suppression of EphA2 expression by long-term exposure to ligand ephrinA1 or EphA2-targeted shRNA inhibited EGF-induced cell proliferation. Stimulation of the cells with EGF induced EphA2 S897 phosphorylation, which was suppressed by MEK and RSK inhibitors, but not by phosphatidylinositol 3-kinase (PI3K) and Akt inhibitors. The RSK inhibitor or RSK2-targeted shRNA also suppressed EGF-induced cell proliferation. Furthermore, overexpression of wild-type EphA2 promoted cell proliferation without EGF stimulation, whereas overexpression of EphA2-S897A mutant suppressed EGF- or RSK2-induced proliferation. Taken together, these results suggest that EphA2 is a key downstream target of the MEK/ERK/RSK signaling pathway in the regulation of glioblastoma cell proliferation. [Display omitted] •EphA2 is involved in EGF-induced glioblastoma cell proliferation.•EGF induces phosphorylation of S897 EphA2 through the MEK/ERK/RSK pathway.•EphA2 S897 phosphorylation is required for EGF-induced cell proliferation.