EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation
EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation
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DOI：
10.1016/j.cellsig.2016.04.009
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发表时间：
2016-08-01
影响因子：
4.8
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
--
作者：
Hamaoka, Yuho;Negishi, Manabu;Katoh, Hironori
EphA 2是Eph受体酪氨酸激酶的成员，在包括胶质母细胞瘤在内的多种恶性肿瘤中经常过表达，并且其表达与不良预后相关。EphA 2通过配体肝配蛋白非依赖性机制作为肿瘤促进剂，其需要EphA 2在丝氨酸897（S897）上的磷酸化，导致增加的细胞迁移和侵袭。在这项研究中，我们表明配体非依赖性EphA 2信号传导发生在MEK/ERK/RSK途径的下游，并介导胶质母细胞瘤细胞中表皮生长因子（EGF）诱导的细胞增殖。通过长期暴露于配体ephrinA 1或EphA 2靶向shRNA抑制EphA 2表达抑制EGF诱导的细胞增殖。用EGF刺激细胞诱导EphA 2 5897磷酸化，其被MEK和RSK抑制剂抑制，但不被磷脂酰肌醇3-激酶（PI 3 K）和Akt抑制剂抑制。RSK抑制剂或RSK 2靶向的shRNA也抑制EGF诱导的细胞增殖。此外，野生型EphA 2的过表达在没有EGF刺激的情况下促进细胞增殖，而EphA 2-S897 A突变体的过表达抑制EGF或RSK 2诱导的增殖。总之，这些结果表明EphA 2是胶质母细胞瘤细胞增殖调节中MEK/ERK/RSK信号传导途径的关键下游靶标。(C)2016 Elsevier Inc. All rights reserved.
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 5897 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. (C) 2016 Elsevier Inc. All rights reserved.