Identification of Serum-Derived Sphingosine-1-Phosphate as a Small Molecule Regulator of YAP
Identification of Serum-Derived Sphingosine-1-Phosphate as a Small Molecule Regulator of YAP
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DOI：
10.1016/j.chembiol.2012.07.005
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发表时间：
2012-08-24
影响因子：
--
通讯作者：
Wu, Xu
中科院分区：
文献类型：
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作者：
Miller, Eric;Yang, Jiayi;Wu, Xu
Hippo信号是一种肿瘤抑制通路，通过磷酸化和抑制转录辅激活因子YAP来调节器官大小和肿瘤发生。在这里，我们发现血清剥夺显著诱导YAP Ser127磷酸化和细胞质保留，独立于细胞-细胞接触。通过化学分离和活性分析，我们鉴定出血清来源的鞘氨醇-1-磷酸（S1P）和溶血磷脂酸（LPA）是YAP的小分子激活剂。S1P通过S1P(2)受体、Rho GTPase激活和F-actin聚合诱导YAP核定位，独立于核心Hippo通路激酶。生物信息学研究也表明，S1P刺激可诱导小鼠肝脏和人胚胎干细胞中YAP靶基因的表达。这些结果揭示了YAP有效的小分子调节因子，提示Si P和LPA可能通过激活YAP来调节细胞增殖和肿瘤发生。
Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that Si P and LPA might modulate cell proliferation and tumorigenesis through YAP activation.