Cited by 1,628Hippo pathway signaling and YAP/TAZProtein Kinase Regulation and GTPase SignalingSphingolipid Metabolism and Signaling

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Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling

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Yu, Fa-Xing, Zhao, Bin, Panupinthu, Nattapon, Jewell, Jenna L., Lian, Ian, Wang, Lloyd H., Zhao, Jiagang, Yuan, Haixin, Tumaneng, Karen, Li, Hairi, Fu, Xiang-Dong, Mills, Gordon B., Guan, Kun-Liang·2012·Cell

DOI 10.1016/j.cell.2012.06.037PMC PMC3433174

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Abstract

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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Authors: Yu, F.-X., Zhao, B., Panupinthu, N., Jewell, J. L., Lian, I., Wang, L. H., Zhao, J., Yuan, H., Tumaneng, K., Li, H., Fu, X.-D., Mills, G. B., & Guan, K.-L.
Affiliations: University of California San Diego (US)
Zhejiang University (CN)
The University of Texas MD Anderson Cancer Center (US)
Corresponding author: Guan, Kun-Liang
ORCID: Yu, Fa-Xing
Zhao, Bin
Panupinthu, Nattapon
Jewell, Jenna L.
Fu, Xiang-Dong
Guan, Kun-Liang
Venue: Cell
Publisher: Elsevier BV
Published: 2012-08
Volume: 150
Issue: 4
Pages: 780-791
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2012.06.037
PMC: PMC3433174
OpenAlex: W2109838283
Cited by: 1,628
References: 48
Citations by year: 2026: 65 · 2025: 96 · 2024: 125 · 2023: 141 · 2022: 135 · 2021: 148 · 2020: 142 · 2019: 134 · 2018: 162 · 2017: 94 · 2016: 104 · 2015: 116 · 2014: 90 · 2013: 61 · 2012: 11
FWCI: 42.14
Type: journal article
Language: en
Update notices: erratum (2024-03-14)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 428 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Eye Institute (R01EY022611)
National Cancer Institute (P30-CA-23100, P50CA098258, R01CA132809, P30CA023100, T32CA121938, P30CA016672)
National Institute of General Medical Sciences (R01GM052872, T32GM007752, GM052872)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords: Hippo signaling pathway, YAP, TAZ, G protein-coupled receptors, lysophosphatidic acid, sphingosine-1-phosphate, LATS1/2 kinases, Gs-coupled receptors, glucagon, epinephrine, organ size control, cell proliferation, cell migration, carcinogenesis
MeSH terms: Acyltransferases, Animals, Cell Line, Cell Movement, Humans, Lysophospholipids, Neoplasms, Nuclear Proteins, Organ Size, Phosphorylation, Sphingosine, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Receptors, G-Protein-Coupled, Serum, Cell Proliferation

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Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor Signaling

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