G protein-coupled receptors can control the Hippo/YAP pathway through Gq signaling.
Activating Transcription Factor 6
/ genetics
Cell Cycle Proteins
/ genetics
GTP-Binding Protein alpha Subunits, G12-G13
/ genetics
GTP-Binding Protein alpha Subunits, Gq-G11
/ genetics
Gene Expression Regulation
HEK293 Cells
Hippo Signaling Pathway
Humans
Phosphorylation
Protein Serine-Threonine Kinases
/ genetics
Receptors, G-Protein-Coupled
/ genetics
Transcription Factors
/ genetics
Ghrelin receptor
Hippo pathway
cellular signaling
constitutive activity
inverse agonist
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
21
04
2021
received:
18
09
2020
accepted:
30
04
2021
entrez:
11
6
2021
pubmed:
12
6
2021
medline:
20
7
2021
Statut:
ppublish
Résumé
The Hippo pathway is an evolutionarily conserved kinase cascade involved in the control of tissue homeostasis, cellular differentiation, proliferation, and organ size, and is regulated by cell-cell contact, apical cell polarity, and mechanical signals. Miss-regulation of this pathway can lead to cancer. The Hippo pathway acts through the inhibition of the transcriptional coactivators YAP and TAZ through phosphorylation. Among the various signaling mechanisms controlling the hippo pathway, activation of G12/13 by G protein-coupled receptors (GPCR) recently emerged. Here we show that a GPCR, the ghrelin receptor, that activates several types of G proteins, including G12/13, Gi/o, and Gq, can activate YAP through Gq/11 exclusively, independently of G12/13. We revealed that a strong basal YAP activation results from the high constitutive activity of this receptor, which can be further increased upon agonist activation. Thus, acting on ghrelin receptor allowed to modulate up-and-down YAP activity, as activating the receptor increased YAP activity and blocking constitutive activity reduced YAP activity. Our results demonstrate that GPCRs can be used as molecular switches to finely up- or down-regulate YAP activity through a pure Gq pathway.
Identifiants
pubmed: 34114695
doi: 10.1096/fj.202002159R
doi:
Substances chimiques
ATF6B protein, human
0
Activating Transcription Factor 6
0
Cell Cycle Proteins
0
Receptors, G-Protein-Coupled
0
Transcription Factors
0
YY1AP1 protein, human
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
GTP-Binding Protein alpha Subunits, G12-G13
EC 3.6.5.1
GTP-Binding Protein alpha Subunits, Gq-G11
EC 3.6.5.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21668Informations de copyright
© 2021 Federation of American Societies for Experimental Biology.
Références
Dong J, Feldmann G, Huang J, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120-1133.
Totaro A, Panciera T, Piccolo S. YAP/TAZ upstream signals and downstream responses. Nat Cell Biol. 2018;20:888-899.
Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 2013;154:1342-1355.
Hong W, Guan K-L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23:785-793.
Lei Q-Y, Zhang H, Zhao B, et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the Hippo pathway. Mol Cell Biol. 2008;28:2426-2436.
Zhao B, Ye X, Yu J, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962-1971.
Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2014;13:63-79.
Liu H, Du S, Lei T, et al. Multifaceted regulation and functions of YAP/TAZ in tumors (Review). Oncol Rep. 2018;40:16-28.
Luo J, Yu F-X. GPCR-hippo signaling in cancer. Cells. 2019;8:426.
Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783-803.
Hiemer SE, Szymaniak AD, Varelas X. The transcriptional regulators TAZ and YAP direct transforming growth factor β-induced tumorigenic phenotypes in breast cancer cells. J Biol Chem. 2014;289:13461-13474.
Nallet-Staub F, Marsaud V, Li L, et al. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in cutaneous melanoma. J Invest Dermatol. 2014;134:123-132.
Wang L, Shi S, Guo Z, et al. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS One. 2013;8:e65539.
Xia Y, Zhang Y-L, Yu C, Chang T, Fan H-Y. YAP/TEAD co-activator regulated pluripotency and chemoresistance in ovarian cancer initiated cells. PLoS One. 2014;9:e109575.
Bartucci M, Dattilo R, Moriconi C, et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2015;34:681-690.
Cordenonsi M, Zanconato F, Azzolin L, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759-772.
Mo J-S, Park HW, Guan K-L. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15:642-656.
Koo JH, Guan K-L. Interplay between YAP/TAZ and Metabolism. Cell Metab. 2018;28:196-206.
Mo J-S, Meng Z, Kim YC, et al. Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol. 2015;17:500-510.
Mo J-S. The role of extracellular biophysical cues in modulating the Hippo-YAP pathway. BMB Rep. 2017;50:71-78.
Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747-2761.
Yang C-C, Graves HK, Moya IM, et al. Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules. Proc Natl Acad Sci USA. 2015;112:1785-1790.
Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474:179-183.
Hansen CG, Moroishi T, Guan K-L. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 2015;25:499-513.
Yu F-X, Zhao B, Panupinthu N, et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150:780-791.
Feng XU, Liu P, Zhou X, et al. Thromboxane A2 activates YAP/TAZ protein to induce vascular smooth muscle cell proliferation and migration. J Biol Chem. 2016;291:18947-18958.
Miller E, Yang J, DeRan M, et al. Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP. Chem Biol. 2012;19:955-962.
Iglesias-Bartolome R, Torres D, Marone R, et al. Inactivation of a Gα(s)-PKA tumour suppressor pathway in skin stem cells initiates basal-cell carcinogenesis. Nat Cell Biol. 2015;17:793-803.
Hot B, Valnohova J, Arthofer E, et al. FZD10-Gα13 signalling axis points to a role of FZD10 in CNS angiogenesis. Cell Signal. 2017;32:93-103.
Mo J-S, Yu F-X, Gong R, Brown JH, Guan K-L. Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes Dev. 2012;26:2138-2143.
Wang J, Sinnett-Smith J, Stevens JV, Young SH, Rozengurt E. Biphasic Regulation of Yes-associated Protein (YAP) cellular localization, phosphorylation, and activity by G protein-coupled receptor agonists in intestinal epithelial cells: a NOVEL ROLE FOR PROTEIN KINASE D (PKD). J Biol Chem. 2016;291:17988-18005.
Zhu H, Cheng X, Niu X, et al. Proton-sensing GPCR-YAP signalling promotes cell proliferation and survival. Int J Biol Sci. 2015;11:1181-1189.
Els S, Schild E, Petersen PS, et al. An aromatic region to induce a switch between agonism and inverse agonism at the ghrelin receptor. J Med Chem. 2012;55:7437-7449.
M’Kadmi C, Cabral A, Barrile F, et al. N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. J Med Chem. 2019;62:965-973.
Zindel D, Vol C, Lecha O, et al. HTRF® Total and Phospho-YAP (Ser127) cellular assays. Methods Mol Biol Clifton NJ. 2019;1893:153-166.
Brulé C, Perzo N, Joubert J-E, et al. Biased signaling regulates the pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. FASEB J. 2014;28:5148-5162.
Camiña JP, Lodeiro M, Ischenko O, Martini AC, Casanueva FF. Stimulation by ghrelin of p42/p44 mitogen-activated protein kinase through the GHS-R1a receptor: role of G-proteins and beta-arrestins. J Cell Physiol. 2007;213:187-200.
Damian M, Mary S, Maingot M, et al. Ghrelin receptor conformational dynamics regulate the transition from a preassembled to an active receptor: Gq complex. Proc Natl Acad Sci USA. 2015;112:1601-1606.
M'Kadmi C, Leyris J-P, Onfroy L, et al. Agonism, antagonism, and inverse agonism bias at the ghrelin receptor signaling. J Biol Chem. 2015;290:27021-27039.
Schrage R, Schmitz A-L, Gaffal E, et al. The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun. 2015;6:10156.
Damian M, Marie J, Leyris J-P, et al. High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. J Biol Chem. 2012;287:3630-3641.
Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Mol Endocrinol Baltim Md. 2003;17:2201-2210.
Moulin A, Demange L, Ryan J, et al. New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem. 2008;51:689-693.
Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283:5496-5509.
Yu F-X, Guan K-L. The Hippo pathway: regulators and regulations. Genes Dev. 2013;27:355-371.
Li Z, Zhao B, Wang P, et al. Structural insights into the YAP and TEAD complex. Genes Dev. 2010;24:235-240.
Finch-Edmondson ML, Strauss RP, Passman AM, Sudol M, Yeoh GC, Callus BA. TAZ protein accumulation is negatively regulated by YAP abundance in mammalian cells. J Biol Chem. 2015;290:27928-27938.
Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992;70:389-399.
Spiering D, Hodgson L. Dynamics of the Rho-family small GTPases in actin regulation and motility. Cell Adhes Migr. 2011;5:170-180.
Gong R, Hong AW, Plouffe SW, et al. Opposing roles of conventional and novel PKC isoforms in Hippo-YAP pathway regulation. Cell Res. 2015;25:985-988.
Hayakawa Y, Sakitani K, Konishi M, et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell. 2017;31:21-34.
Zhou X, Wang S, Wang Z, et al. Estrogen regulates Hippo signaling via GPER in breast cancer. J Clin Invest. 2015;125:2123-2135.
Van Raamsdonk CD, Bezrookove V, Green G, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457:599-602.
Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med. 2010;363:2191-2199.
Feng X, Degese M, Iglesias-Bartolome R, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014;25:831-845.
Feng X, Arang N, Rigiracciolo DC, et al. A platform of synthetic lethal gene interaction networks reveals that the GNAQ uveal melanoma oncogene controls the hippo pathway through FAK. Cancer Cell. 2019;35:457-472.e5.
Ango F, Albani-Torregrossa S, Joly C, et al. A simple method to transfer plasmid DNA into neuronal primary cultures: functional expression of the mGlu5 receptor in cerebellar granule cells. Neuropharmacology. 1999;38:793-803.
Davenport AP, Bonner TI, Foord SM, et al. International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev. 2005;57:541-546.
Kim SW, Her SJ, Park SJ, et al. Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone. 2005;37:359-369.
Lee JH, Patel K, Tae HJ, et al. Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways. FEBS Lett. 2014;588:4708-4719.
Wang Q, Zheng M, Yin Y, Zhang W. Ghrelin stimulates hepatocyte proliferation via regulating cell cycle through GSK3β/Β-catenin signaling pathway. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2018;50:1698-1710.
Waseem T, Javaid-ur-Rehman, Ahmad F, Azam M, Qureshi MA. Role of ghrelin axis in colorectal cancer: a novel association. Peptides. 2008;29:1369-1376.
Lin T-C, Liu Y-P, Chan Y-C, et al. Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. J Pathol. 2015;237:50-61.
Northrup R, Kuroda K, Duus EM, et al. Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model. Support Care Cancer. 2013;21:2409-2415.
Currow D, Temel JS, Abernethy A, Milanowski J, Friend J, Fearon KC. ROMANA 3: a phase 3 safety extension study of anamorelin in advanced non-small-cell lung cancer (NSCLC) patients with cachexia. Ann Oncol. 2017;28:1949-1956.
Soleyman-Jahi S, Sadeghi F, Pastaki Khoshbin A, Khani L, Roosta V, Zendehdel K. Attribution of Ghrelin to cancer; attempts to unravel an apparent controversy. Front Oncol. 2019;9:1-25.