Miller Eric, Yang Jiayi, DeRan Michael, Wu Chunlei, Su Andrew I, Bonamy Ghislain M C, Liu Jun, Peters Eric C, Wu Xu
Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Chem Biol. 2012 Aug 24;19(8):955-62. doi: 10.1016/j.chembiol.2012.07.005. Epub 2012 Aug 9.
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 S1P and LPA might modulate cell proliferation and tumorigenesis through YAP activation.
Hippo信号通路是一种肿瘤抑制途径，通过磷酸化和抑制转录共激活因子YAP来调节器官大小和肿瘤发生。在此，我们表明血清剥夺可显著诱导YAP Ser127磷酸化和细胞质滞留，且与细胞间接触无关。通过化学分离和活性分析，我们鉴定出血清衍生的1-磷酸鞘氨醇（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-肌动蛋白聚合诱导YAP核定位，与核心Hippo途径激酶无关。生物信息学研究还表明，S1P刺激可诱导小鼠肝脏和人类胚胎干细胞中YAP靶基因的表达。这些结果揭示了YAP的有效小分子调节剂，并表明S1P和LPA可能通过激活YAP来调节细胞增殖和肿瘤发生。
