College of Biotechnology and Bioengineering, Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, Republic of Korea.
Stem Cells Dev. 2020 Sep 15;29(18):1240-1246. doi: 10.1089/scd.2019.0281. Epub 2020 Aug 12.
The Hippo signaling pathway regulates cell proliferation and organ growth, and its activation is mainly reflected by the phosphorylation levels of Yes-associated protein (YAP). In this study, we show that YAP facilitates embryonic neural stem cell proliferation by elevating their responsiveness to fibroblast growth factor 2 (FGF2), one of the major growth factors for neural stem cells, in vivo as well as in vitro. Western blot and quantitative real-time PCR analyses revealed that expression of the FGF receptors (FGFRs) to were greatly increased by YAP expression upon FGF2 treatment, followed by upregulation of the mitogen-activated protein kinase and protein kinase B signaling pathways. Furthermore, as assessed by quantitative real-time PCR analyses, YAP-induced expression was found to be TEA domain transcription factor (TEAD)-independent, and transcriptional coactivator with PDZ-binding motif, the other homolog of Yorki in the Hippo signaling pathway, was found to possess similar activity to YAP. Finally, adjustment of FGFR signaling activity in the YAP-expressing cells to control levels efficiently offset the cell proliferative effects of YAP, suggesting that the increased proliferation of YAP-expressing neural stem cells was mainly attributable to enhanced FGFR signaling. Our data indicate that YAP plays an important role in neural stem cell regulation by elevating FGFR expression, subsequently leading to enhanced cell proliferation.
Hippo 信号通路调节细胞增殖和器官生长，其激活主要反映在 Yes 相关蛋白 (YAP) 的磷酸化水平上。在这项研究中，我们表明 YAP 通过提高其对成纤维细胞生长因子 2（FGF2）的反应性，在体内和体外促进胚胎神经干细胞的增殖。FGF2 是神经干细胞的主要生长因子之一。Western blot 和定量实时 PCR 分析表明，YAP 表达后，FGF2 处理可大大增加 FGFRs（FGFRs）的表达，随后激活丝裂原活化蛋白激酶和蛋白激酶 B 信号通路。此外，通过定量实时 PCR 分析发现，YAP 诱导的 表达与 TEA 结构域转录因子（TEAD）无关，而在 Hippo 信号通路中与 Yorki 为同源物的 PDZ 结合基序转录共激活因子，被发现具有类似于 YAP 的活性。最后，调整 YAP 表达细胞中 FGFR 信号活性至对照水平可有效抵消 YAP 的细胞增殖效应，表明 YAP 表达的神经干细胞增殖增加主要归因于增强的 FGFR 信号。我们的数据表明，YAP 通过提高 FGFR 表达在神经干细胞调节中发挥重要作用，进而导致细胞增殖增强。
