Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2α.
Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2α.
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DOI：
10.1371/journal.pone.0128826
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sakaguchi K
中科院分区：
文献类型：
--
作者：
Sawada T;Arai D;Jing X;Furushima K;Chen Q;Kawakami K;Yokote H;Miyajima M;Sakaguchi K
Ephs和FGFRs属于受体酪氨酸激酶超家族，在干细胞生物学中发挥着重要作用。我们以前报道过，EphA4和FGFR在受到配体刺激后形成异源二聚体，相互反式激活，并通过与两个受体结合的对接蛋白FRS2α发出信号。在这里，我们研究了EphA4和FGFRs之间的相互作用是否可以推广到其他Ephs和FGFRs，此外，我们还研究了在胚胎神经干细胞/祖细胞中介导它们功能的下游信号。我们发现不同的Ephs和FGFR通过相似的分子结构域相互作用。当神经干/祖细胞受到成纤维细胞生长因子2和肾上腺素A1刺激时，EphA4/FGFR/FRS2α复合体传递的信号促进了神经干细胞的自我更新，而单独使用肾上腺素A1刺激则诱导神经元分化。神经元分化所需的下游信号似乎是MAP激酶，主要与RAS家族的G蛋白相连。与FGF2诱导的一过性激活不同，MAPK的激活是延迟和持续的。有趣的是，这种对神经元分化的影响需要FGFRs的存在。特异性的FGFR拮抗剂几乎完全取消了肾上腺素-A1的刺激作用。这些结果表明，配体刺激形成的EphA、FGFR和FRS2α三元复合体通过FRS2α对下游信号进行配体特异性的微调，从而调控小鼠胚胎神经干/祖细胞的自我更新和分化。
Ephs and FGFRs belong to a superfamily of receptor tyrosine kinases, playing important roles in stem cell biology. We previously reported that EphA4 and FGFR form a heterodimer following stimulation with ligands, trans-activating each other and signaling through a docking protein, FRS2α, that binds to both receptors. Here, we investigated whether the interaction between EphA4 and FGFRs can be generalized to other Ephs and FGFRs, and, in addition, examined the downstream signal mediating their function in embryonic neural stem/progenitor cells. We revealed that various Ephs and FGFRs interact with each other through similar molecular domains. When neural stem/progenitor cells were stimulated with FGF2 and ephrin-A1, the signal transduced from the EphA4/FGFR/FRS2α complex enhanced self-renewal, while stimulation with ephrin-A1 alone induced neuronal differentiation. The downstream signal required for neuronal differentiation appears to be MAP kinase mainly linked to the Ras family of G proteins. MAP kinase activation was delayed and sustained, distinct from the transient activation induced by FGF2. Interestingly, this effect on neuronal differentiation required the presence of FGFRs. Specific FGFR inhibitor almost completely abolished the function of ephrin-A1 stimulation. These findings suggest that the ternary complex of EphA, FGFR and FRS2α formed by ligand stimulation regulates self-renewal and differentiation of mouse embryonic neural stem/progenitor cells by ligand-specific fine tuning of the downstream signal via FRS2α.
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影响因子：
3.7
作者：
Jing X;Miwa H;Sawada T;Nakanishi I;Kondo T;Miyajima M;Sakaguchi K
通讯作者：
Sakaguchi K
影响因子：
29
作者：
Zhao, Chen;Irie, Naoko;Matsuo, Koichi
通讯作者：
Matsuo, Koichi
影响因子：
14.8
作者：
Ferron, Sacri R.;Andreu-Agullo, Celia;Farinas, Isabel
通讯作者：
Farinas, Isabel
影响因子：
64.5
作者：
Shamah, SM;Lin, MZ;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1073/pnas.0507961102
发表时间：
2005-11-01
影响因子：
11.1
作者：
Yamamoto, S;Yoshino, I;Gotoh, N
通讯作者：
Gotoh, N