RRC ID 47923
著者 Hamaoka Y, Negishi M, Katoh H.
タイトル EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation.
ジャーナル Cell Signal
Abstract 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.
巻・号 28(8)
ページ 937-45
公開日 2016-8-1
DOI 10.1016/j.cellsig.2016.04.009
PII S0898-6568(16)30095-X
PMID 27132626
MeSH Brain Neoplasms / enzymology* Brain Neoplasms / pathology* Bromodeoxyuridine / metabolism Cell Line, Tumor Cell Proliferation / drug effects Epidermal Growth Factor / pharmacology 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* Signal Transduction / drug effects
IF 3.968
引用数 26
WOS 分野 CELL BIOLOGY
リソース情報
ヒト・動物細胞 A172(RCB2530) MKN45(RCB1001)