Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.
Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.
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DOI：
10.1016/j.cell.2012.06.037
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发表时间：
2012-08-17
期刊：
影响因子：
64.5
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Yu FX;Zhao B;Panupinthu N;Jewell JL;Lian I;Wang LH;Zhao J;Yuan H;Tumaneng K;Li H;Fu XD;Mills GB;Guan KL
Hippo通路在器官大小控制中至关重要，其失调有助于肿瘤发生。然而，调节哺乳动物Hippo通路的上游信号仍然难以捉摸。在这里，我们报告说，海马通路的G蛋白偶联受体（GPCR）信号调节。血清携带的溶血磷脂酸（LPA）和1-磷酸鞘氨醇（S1 P）通过G12/13偶联受体发挥作用，抑制Hippo途径激酶Lats 1/2，从而激活雅普和TAZ转录共激活因子，这是受Lats 1/2抑制的癌蛋白。雅普和TAZ参与LPA诱导的基因表达、细胞迁移和增殖。相反，胰高血糖素或肾上腺素刺激Gs偶联受体可激活Lats 1/2激酶活性，从而抑制雅普功能。因此，GPCR信号可以激活或抑制Hippo-YAP途径，这取决于偶联的G蛋白。我们的研究鉴定了调节Hippo通路的细胞外扩散信号，并将Hippo-YAP通路确立为GPCR下游的关键信号传导分支。
The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here we report that the Hippo pathway is regulated by G-protein coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2 thereby activating YAP and TAZ transcription co-activators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G-protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR.
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