Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge.
Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge.
复制标题
DOI：
10.3389/fmed.2015.00059
复制
发表时间：
2015
影响因子：
3.9
通讯作者：
Boersema M
中科院分区：
文献类型：
--
作者：
Piersma B;Bank RA;Boersema M
慢性器官损伤导致纤维化并最终导致器官衰竭。纤维化的特征在于由肌成纤维细胞产生的细胞外基质的过度合成、重塑和收缩。肌成纤维细胞是纤维化疾病的病理生理学中的关键细胞，并且其分化可由多种刺激触发。为了开发抗纤维化疗法，理解有助于肌成纤维细胞活化和维持的信号通路的分子基础是至关重要的。一些信号转导途径，如转化生长因子（TGF）-β、无翅/Int（WNT）和最近的具有PDZ结合基序的转录共激活因子（TAZ）信号转导的yes相关蛋白1（雅普）/转录共激活因子（TAZ），已经与纤维化的病理生理学相关。TGF-β1诱导的SMAD复合物的激活导致对肌成纤维细胞功能重要的基因的上调。类似地，WNT稳定的β-连环蛋白易位到细胞核并启动其靶基因的转录。雅普和TAZ是来自Hippo信号传导途径的两种转录共激活因子，其功能也依赖于核转位。这三种信号转导途径几乎没有分子相似性，但有一个共同的原则：其转录激活因子的胞质/核调节。过去对这些通路的研究往往集中在孤立的级联反应，而没有考虑到其他信号通路。最近的发展表明，这些途径的一部分汇聚成一个复杂的网络，管理肌成纤维细胞表型的激活和维持。本文就TGF-β、WNT和雅普/TAZ信号通路在器官纤维化发生发展中的整合作用作一综述。采取网络范围内的信号转导的观点将提供一个更好的理解纤维化疾病的病理生理学基础的复杂和多功能的过程。
Chronic organ injury leads to fibrosis and eventually organ failure. Fibrosis is characterized by excessive synthesis, remodeling, and contraction of extracellular matrix produced by myofibroblasts. Myofibroblasts are the key cells in the pathophysiology of fibrotic disorders and their differentiation can be triggered by multiple stimuli. To develop anti-fibrotic therapies, it is of paramount importance to understand the molecular basis of the signaling pathways contributing to the activation and maintenance of myofibroblasts. Several signal transduction pathways, such as transforming growth factor (TGF)-β, Wingless/Int (WNT), and more recently yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling, have been linked to the pathophysiology of fibrosis. Activation of the TGF-β1-induced SMAD complex results in the upregulation of genes important for myofibroblast function. Similarly, WNT-stabilized β-catenin translocates to the nucleus and initiates transcription of its target genes. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway that also rely on nuclear translocation for their functioning. These three signal transduction pathways have little molecular similarity but do share one principle: the cytosolic/nuclear regulation of its transcriptional activators. Past research on these pathways often focused on the isolated cascades without taking other signaling pathways into account. Recent developments show that parts of these pathways converge into an intricate network that governs the activation and maintenance of the myofibroblast phenotype. In this review, we discuss the current understanding on the signal integration between the TGF-β, WNT, and YAP/TAZ pathways in the development of organ fibrosis. Taking a network-wide view on signal transduction will provide a better understanding on the complex and versatile processes that underlie the pathophysiology of fibrotic disorders.