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首页> 外文期刊>Journal of cellular physiology. >GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7
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GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7

机译：GPCR-mediated YAP /小胡子在成纤维细胞失活通过EPAC1/2 RAP2C, MAP4K7

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摘要

Yes-associated protein (YAP) and PDZ-binding motif (TAZ) have emerged as important regulators of pathologic fibroblast activation in fibrotic diseases. Agonism of Gas-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.
机译：Yes-associated蛋白质(笨蛋)和PDZ-binding图案(小胡子)已成为重要的监管机构病理纤维化的成纤维细胞活化疾病。耦合的受体(GPCRs)提供了一个有吸引力的核本地化和抑制方法函数YAP和小胡子的成纤维细胞抑制或逆转他们的病态激活。被证明有效的临床前模型的肺和肝纤维化。机制耦合GPCR激动YAP和小胡子成纤维细胞失活仍不完全理解。我们确定了营地的效应器的关键角色EPAC1/2,小GTPase RAP2c,丝氨酸/苏氨酸激酶MAP4K7至关重要元素的下游信号级联连接GPCR LATS1/2-mediated YAP和激动小胡子磷酸化和核排斥成纤维细胞。EPAC / RAP2c MAP4K7信号级联是至关重要的多巴胺D1受体激动的影响减少成纤维细胞增殖,收缩,和细胞外基质生产。调制的级联成纤维细胞证明一个有用的策略来调节狂吠,小胡子信号和纤维母细胞活动的中心组织修复和纤维化。

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