Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling

By Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu, Jenna L. Jewell, Ian Y. Lian, Lloyd H. Wang, Jiagang J. Zhao, Hai‐Xin Yuan, K. Tumaneng, Hai-Ri Li and 3 more. Cell, 2012

1,568 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/caccb25f91deefaa817e2afc8b7bbada53d9d2b7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. K. Guan
2. S. Piccolo
3. Fa-Xing Yu
4. M. Cordenonsi
5. Z. Meng
6. S. Dupont
7. H. Park
8. Jung-Soon Mo

In Molecular Biology

1. K. Guan
2. E. Olson
3. S. Piccolo
4. Fa-Xing Yu
5. M. Cordenonsi
6. Duojia Pan
7. Xaralabos Varelas
8. Young Chul Kim

Citations in the corpus

• The Hippo signaling pathway in stem cell biology and cancer (2014, neutral): “Moreover, the Hippo pathway is potently and acutely regulated by a wide array of extracellular hormones, including lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), epinephrine, glucagon, and thrombin [53 – 55].”
• The Hippo Pathway: Biology and Pathophysiology. (2019, background): “Specifically, ligand signaling through GPCRs coupled to Gα12/13, Gαi/o, or Gαq/11, such as LPA, thrombin, angiotensin II, and estrogen, activates YAP/TAZ; in contrast, ligand signaling through GPCRs coupled to Gαs, such as glucagon and epinephrine, suppresses YAP/TAZ activity (93, 124).”
• The biology of YAP/TAZ: hippo signaling and beyond. (2014, background): “This correlates with the fact that LATS1/2 show reduced kinase activity upon Rho inhibition (246).”
• YAP/TAZ at the roots of cancer (2016, background): “The discovery of RhoGTPases as global regulators of YAP/TAZ activity prompted the intriguing discovery that soluble ligands signaling through GPCR and Rho can promote YAP/TAZ nuclear localization and transcriptional activities (Yu et al., 2012) (Figure 3).”
• LPA receptor signaling: pharmacology, physiology, and pathophysiology (2014, background): “through G13 stimulation, presumably via the RhoA-ROCK pathway, while Gs activity inhibited YAP function (110, 111).”
• The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease (2014, background): “Conversely, stimulation of Gαs-coupled GPCRs with hormones, such as epinephrine or glucagon, increases LATS1/2-mediated phosphorylation of YAP, thereby decreasing nuclear YAP activity (Yu et al., 2012).”
• Hippo pathway effector Yap promotes cardiac regeneration (2013, background): “Recently, signals from different G protein-coupled receptors were shown to exert antagonistic effects on this pathway, depending on the ligand and the coupled G protein (22).”
• The Hippo signalling pathway and its implications in human health and diseases (2022, background): “26 However, when the Hippo pathway is activated, MAP4Ks, MST1/2 and its scaffold protein SAV1 phosphorylate LATS1/2 and its scaffold MOB1A/B. 27 Then, activated LATS1/2 phosphorylates and inhibits YAP and TAZ, preventing them from translocating into the nucleus to interact with TEAD 1 – 4.”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, neutral): “Supporting a role for LATS1/2, the phosphorylation status and in vitro kinase activity of LATS1/2 are clearly regulated upon actin cytoskeleton rearrangement, and the kinetics are similar to that of YAP/TAZ phosphorylation (Yu et al., 2012; Zhao et al., 2012).”
• Alternative Wnt Signaling Activates YAP/TAZ (2015, background): “Recent studies uncovered the critical role of GPCR signaling in YAP/TAZ regulation (Miller et al., 2012; Mo et al., 2012; Yu et al., 2012, 2014b), as well as crosstalk with Wnt or TGFb signaling (Moroishi et al., 2015; Piccolo et al., 2014).”