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通过G蛋白结合受体信号传递来调节Hippo-YAP通路
Fa-Xing Yu1, Bin Zhao, Nattapon Panupinthu
1Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
G-蛋白结合受体 (GPCR) 信号调节Hippo路径. 像LPA和S1P这样的细胞外信号可以抑制或激活Hippo-YAP信号,影响癌症中的细胞生长和迁移.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 在瘤学瘤学.
背景情况:
- 河马通路对于器官大小控制至关重要,其失调与癌症有关.
- 哺乳动物河马通路的上游调节者仍然在很大程度上是未知的.
- 河马通路的核心激酶,Lats1/2,抑制了YAP和TAZ,这是关键的转录协活性剂.
研究的目的:
- 为了识别调节哺乳动物河马路径的上游信号.
- 为了研究G蛋白结合受体 (GPCR) 信号传导在Hippo通路调节中的作用.
- 阐明GPCRs如何调节YAP和TAZ活动.
主要方法:
- 研究了特定的GPCR配体 (LPA,S1P,葡萄糖,上腺素) 对Hippo通路组件的影响.
- 利用基于细胞的测试来监测Lats1/2.2.的激酶活性.
- 评估了对YAP/TAZ转录活动和下游细胞过程,如迁移和增殖的影响.
主要成果:
- GPCR信号直接调节了河马的通路.
- Lysophosphatidic 酸 (LPA) 和斯芬戈辛1-酸盐 (S1P) 通过G12/13合受体发出信号,抑制Lats1/2,激活YAP/TAZ.
- 葡萄糖和上腺素通过Gs合受体发出信号来激活Lats1/2,抑制YAP功能.
- YAP/TAZ调解LPA诱导的基因表达,细胞迁移和增殖.
结论:
- GPCR信号传递作为Hippo-YAP通路的关键上游调节器.
- 河马-YAP通路是GPCRs的一个关键下游信号分支.
- 细胞外信号调节Hippo通路的活动,在癌症中提供潜在的治疗点.
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