Necdin controls EGFR signaling linked to astrocyte differentiation in primary cortical progenitor cells
Necdin controls EGFR signaling linked to astrocyte differentiation in primary cortical progenitor cells
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DOI：
10.1016/j.cellsig.2015.11.016
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发表时间：
2016-02-01
影响因子：
4.8
通讯作者：
Yoshikawa, Kazuaki
中科院分区：
文献类型：
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作者：
Fujimoto, Izumi;Hasegawa, Koichi;Yoshikawa, Kazuaki
表皮生长因子受体（EGFR）介导的细胞信号在控制皮质祖细胞（CPC）的增殖和分化中起着关键作用。然而，EGFR信号转导在CPC中的调节机制在很大程度上仍然未知。在这里，我们证明necdin，一个法师（黑色素瘤抗原）家族蛋白，与表皮生长因子受体在原代CPC相互作用，并抑制其下游信号与星形胶质细胞分化。表皮生长因子受体是自磷酸化和相互作用的necdin在表皮生长因子刺激的CPC。Necdin通过其酪氨酸激酶结构域与自磷酸化EGFR结合。EGF诱导的ERK磷酸化在necdin-null CPC中增强，其中EGFR和衔接蛋白Grb2之间的相互作用增强，表明内源性necdin抑制CPC中的EGFR/ERK信号通路。在necdin无效CPC，星形胶质细胞分化诱导的胶质细胞因子心肌营养素-1在EGF的存在下显着加速，抑制EGFR/ERK信号消除加速。此外，necdin强烈抑制由EGFR或其配体结合缺陷突变体（相当于胶质母细胞瘤相关EGFR变体）过度表达诱导的星形胶质细胞分化。这些结果表明，necdin作为一个内在的抑制剂的EGFR/ERK信号通路在EGF反应的CPC抑制星形胶质细胞的发展，在细胞自主的方式。(C)2015年，作者。爱思唯尔公司出版这是一个在CC BY-NC-ND许可下的开放获取文章
Cellular signaling mediated by the EGF receptor (EGFR) plays a key role in controlling proliferation and differentiation of cortical progenitor cells (CPCs). However, regulatory mechanisms of EGFR signaling in CPCs remain largely unknown. Here we demonstrate that necdin, a MAGE (melanoma antigen) family protein, interacts with EGFR in primary CPCs and represses its downstream signaling linked to astrocyte differentiation. EGFR was autophosphorylated and interacted with necdin in EGF-stimulated CPCs. Necdin bound to autophosphorylated EGFR via its tyrosine kinase domain. EGF-induced phosphorylation of ERK was enhanced in necdin-null CPCs, where the interaction between EGFR and the adaptor protein Grb2 was strengthened, suggesting that endogenous necdin suppresses the EGFR/ERK signaling pathway in CPCs. In necdin-null CPCs, astrocyte differentiation induced by the gliogenic cytokine cardiotrophin-1 was significantly accelerated in the presence of EGF, and inhibition of EGFR/ERK signaling abolished the acceleration. Furthermore, necdin strongly suppressed astrocyte differentiation induced by overexpression of EGFR or its ligand binding-defective mutant equivalent to a glioblastoma-associated EGFR variant. These results suggest that necdin acts as an intrinsic suppressor of the EGFR/ERK signaling pathway in EGF-responsive CPCs to restrain astroglial development in a cell-autonomous manner. (C) 2015 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license