PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis.
PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis.
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DOI：
10.1038/ncomms12502
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发表时间：
2016-08-18
影响因子：
16.6
通讯作者：
Piper Hanley K
中科院分区：
文献类型：
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作者：
Martin K;Pritchett J;Llewellyn J;Mullan AF;Athwal VS;Dobie R;Harvey E;Zeef L;Farrow S;Streuli C;Henderson NC;Friedman SL;Hanley NA;Piper Hanley K
由肌成纤维细胞分泌的细胞外基质（ECM）引起的纤维化使许多慢性肝脏疾病复杂化，导致疤痕和器官衰竭。整合素依赖性与疤痕ECM的相互作用促进促纤维化特征。然而，肝肌成纤维细胞的病理细胞内机制尚不完全清楚，进一步的了解可以使治疗努力逆转纤维化。在这里，我们发现整合素β -1，能够结合整合素α -11，调节肌成纤维细胞的促纤维化表型。体内促纤维化肌成纤维细胞中整合素β -1的表达上调，在体外，整合素β -1是纤维化ECM成分产生、肌成纤维细胞增殖、迁移和收缩所必需的。丝氨酸/苏氨酸蛋白激酶蛋白，也被称为p21活化激酶（PAK）和机械敏感因子，yes相关蛋白1 （YAP-1）是促纤维化整合素β -1信号传导的核心介质，YAP-1能够使整合素β -1的表达永续。体内任一途径的药理抑制均可减轻肝纤维化。特别是PAK蛋白抑制，可以显著地使促纤维化肌成纤维细胞表型失活，限制不同肝脏损伤造成的疤痕，并代表了治疗肝纤维化的一个新的可处理的治疗靶点。治疗慢性肝病需要靶向肌成纤维细胞活化的抗纤维化疗法。在这里，作者确定了整合素β -1表达轴和Yap-1和Pak蛋白信号传导轴，可以干扰其抑制肌成纤维细胞功能和体内肝纤维化。
Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis. Antifibrotic therapies that target myofibroblast activation are needed to treat chronic liver disease. Here the authors identify an axis of integrin beta-1 expression and Yap-1 and Pak protein signalling that can be interfered with to inhibit myofibroblast function and liver fibrosis in vivo.