TY - JOUR
T1 - Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling
AU - Yu, Fa Xing
AU - Zhao, Bin
AU - Panupinthu, Nattapon
AU - Jewell, Jenna L.
AU - Lian, Ian
AU - Wang, Lloyd H.
AU - Zhao, Jiagang
AU - Yuan, Haixin
AU - Tumaneng, Karen
AU - Li, Hairi
AU - Fu, Xiang Dong
AU - Mills, Gordon B.
AU - Guan, Kun Liang
N1 - Funding Information:
We thank Drs. Jack Dixon, Edward Dennis, Joan Heller Brown, and Jerold Chun for constructive comments; Dr. Rick Neubig for several G protein constructs; Drs. Ji Zhang, Richard Rivera, Zhongrui Zhou, Sunny Xiang, Andrew Markley, Dong Zhang, and Richard Harkewicz for technical help; and Jean Guan and Drs. Yanhui Xu and Ryan Russell for critical reading of the manuscript. This work was supported by grants from NIH and CIRM to K.-L.G. and GM052872 to X.-D.F. and a grant from Breast Cancer Research Foundation to G.B.M. J.L.J. was supported by the National Cancer Institute Training Grant T32CA121938. The cost of confocal imaging was partially supported by NIH Grant P30 CA23100.
PY - 2012/8/17
Y1 - 2012/8/17
N2 - 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 coactivators, 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.
AB - 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 coactivators, 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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U2 - 10.1016/j.cell.2012.06.037
DO - 10.1016/j.cell.2012.06.037
M3 - Article
C2 - 22863277
AN - SCOPUS:84865260845
SN - 0092-8674
VL - 150
SP - 780
EP - 791
JO - Cell
JF - Cell
IS - 4
ER -