GPCR‐mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7. Issue 11 (28th May 2021)

• Record Type: Journal Article
• Authors: Choi, Kyoung Moo; Haak, Andrew J.; Diaz Espinosa, Ana M.; Cummins, Katherine A.; Link, Patrick A.; Aravamudhan, Aja; Wood, David K.; Tschumperlin, Daniel J.
• Is Part Of: Journal of cellular physiology. Volume 236:Issue 11(2021)
• Page Start: 7759
• Page End: 7774
• Publication Date: 2021-05-28
• Subjects: cAMP -- dihydrexidine -- dopamine -- DRD1 -- fibrosis -- Hippo; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.30459
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Yes‐associated protein (YAP) and PDZ‐binding motif (TAZ) have emerged as important regulators of pathologic fibroblast activation in fibrotic diseases. Agonism of Gαs‐coupled G protein coupled receptors (GPCRs) provides an attractive approach to inhibit the nuclear localization and function of YAP and TAZ in fibroblasts that inhibits or reverses their pathological activation. Agonism of the dopamine D1 GPCR has proven effective in preclinical models of lung and liver fibrosis. However, the molecular mechanisms coupling GPCR agonism to YAP and TAZ inactivation in fibroblasts remain incompletely understood. Here, using human lung fibroblasts, we identify critical roles for the cAMP effectors EPAC1/2, the small GTPase RAP2c, and the serine/threonine kinase MAP4K7 as the essential elements in the downstream signaling cascade linking GPCR agonism to LATS1/2‐mediated YAP and TAZ phosphorylation and nuclear exclusion in fibroblasts. We further show that this EPAC/RAP2c/MAP4K7 signaling cascade is essential to the effects of dopamine D1 receptor agonism on reducing fibroblast proliferation, contraction, and extracellular matrix production. Targeted modulation of this cascade in fibroblasts may prove a useful strategy to regulate YAP and TAZ signaling and fibroblast activities central to tissue repair and fibrosis. Abstract : Yes‐associated protein (YAP) and PDZ‐binding motif (TAZ) have emerged as important regulators of pathologic fibroblast activation in fibrotic diseases, and agonism of the dopamine D1 G protein coupled receptor (GPCR) has proven effective in blocking YAP/TAZ and reducing fibrosis. Here we show essential roles for the cyclic adenosine monophosphate effectors EPAC1/2, the small GTPase RAP2c, and the serine/threonine kinase MAP4K7 as essential elements in the downstream signaling cascade linking GPCR agonism to LATS1/2‐mediated YAP and TAZ phosphorylation and nuclear exclusion in fibroblasts.