TGF-β-activated kinase-1: New insights into the mechanism of TGF-β signaling and kidney disease.
TGF-β-activated kinase-1: New insights into the mechanism of TGF-β signaling and kidney disease.
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TGF-β激活的激酶1：对TGF-β信号传导和肾脏疾病机制的新见解。
DOI：
10.1016/j.krcp.2012.04.322
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发表时间：
2012-06
影响因子：
3
通讯作者：
Choi ME
中科院分区：
文献类型：
--
作者：
Kim SI;Choi ME
转化生长因子-β（TGF-β）是一种多功能细胞因子，其调节多种细胞功能，包括细胞生长、细胞分化、凋亡和伤口愈合。TGF-β1是TGF-β超家族的原型成员，被公认为肾纤维化的中心介质。在慢性肾脏疾病中，TGF-β1的表达和活化的失调导致细胞外基质蛋白的不断合成和积累，导致肾小球硬化和肾小管间质纤维化的发展，并最终导致终末期肾脏疾病。因此，特异性靶向TGF-β信号通路似乎是慢性肾脏疾病中有吸引力的分子治疗策略。越来越多的证据表明，TGF-β1的多功能性与其细胞信号网络的复杂性有关。TGF-β1通过I型和II型受体的相互作用发出信号，以激活不同的细胞内途径。虽然Smad信号通路被认为是TGF-β1诱导的经典信号通路，并且已经成为许多先前综述的焦点，但重要的是TGF-β1也诱导各种Smad非依赖性信号通路。在这篇综述中，我们描述了支持目前对TGF-β激活的激酶1（TAK 1）的机制和功能的见解的证据，TAK 1已成为TGF-β诱导的Smad非依赖性信号通路中的关键信号分子。我们还讨论了TAK 1在介导TGF-β1的促纤维化作用中的功能作用。
Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates a wide variety of cellular functions, including cell growth, cellular differentiation, apoptosis, and wound healing. TGF-β1, the prototype member of the TGF-β superfamily, is well established as a central mediator of renal fibrosis. In chronic kidney disease, dysregulation of expression and activation of TGF-β1 results in the relentless synthesis and accumulation of extracellular matrix proteins that lead to the development of glomerulosclerosis and tubulointerstitial fibrosis, and ultimately to end-stage renal disease. Therefore, specific targeting of the TGF-β signaling pathway is seemingly an attractive molecular therapeutic strategy in chronic kidney disease. Accumulating evidence demonstrates that the multifunctionality of TGF-β1 is connected with the complexity of its cell signaling networks. TGF-β1 signals through the interaction of type I and type II receptors to activate distinct intracellular pathways. Although the Smad signaling pathway is known as a canonical pathway induced by TGF-β1, and has been the focus of many previous reviews, importantly TGF-β1 also induces various Smad-independent signaling pathways. In this review, we describe evidence that supports current insights into the mechanism and function of TGF-β-activated kinase 1 (TAK1), which has emerged as a critical signaling molecule in TGF-β-induced Smad-independent signaling pathways. We also discuss the functional role of TAK1 in mediating the profibrotic effects of TGF-β1.