Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
Department of Biomedical Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
J Cell Physiol. 2021 Nov;236(11):7759-7774. doi: 10.1002/jcp.30459. Epub 2021 May 28.
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.
Yes 相关蛋白 (YAP) 和 PDZ 结合基序 (TAZ) 已成为纤维化疾病中病理性成纤维细胞激活的重要调节因子。Gαs 偶联的 G 蛋白偶联受体 (GPCR) 的激动剂提供了一种有吸引力的方法来抑制成纤维细胞中 YAP 和 TAZ 的核定位和功能，从而抑制或逆转它们的病理性激活。多巴胺 D1 GPCR 的激动剂已被证明在肺纤维化和肝纤维化的临床前模型中有效。然而，将 GPCR 激动剂与成纤维细胞中 YAP 和 TAZ 失活偶联的分子机制仍不完全清楚。在这里，我们使用人肺成纤维细胞，确定 cAMP 效应物 EPAC1/2、小 GTPase RAP2c 和丝氨酸/苏氨酸激酶 MAP4K7 作为将 GPCR 激动剂与 LATS1/2 介导的 YAP 和 TAZ 磷酸化和核排除偶联的下游信号级联中的关键作用，在成纤维细胞中。我们进一步表明，这种 EPAC/RAP2c/MAP4K7 信号级联对于多巴胺 D1 受体激动剂减少成纤维细胞增殖、收缩和细胞外基质产生的作用至关重要。靶向调节成纤维细胞中的这种级联可能是调节 YAP 和 TAZ 信号和纤维化中组织修复和纤维化的成纤维细胞活性的有用策略。
