Abstract

Transforming growth factor β (TGF-β) family members play an extensive role in cellular communication that orchestrates both early development and adult tissue homeostasis. Aberrant TGF-β family signaling is associated with a pathological outcome in numerous diseases, and in-depth understanding of molecular and cellular processes could result in therapeutic benefit for patients. Canonical TGF-β signaling is mediated by receptor-regulated SMADs (R-SMADs), a single co-mediator SMAD (Co-SMAD), and inhibitory SMADs (I-SMADs). SMAD7, one of the I-SMADs, is an essential negative regulator of the pleiotropic TGF-β and bone morphogenetic protein (BMP) signaling pathways. In a negative feedback loop, SMAD7 inhibits TGF-β signaling by providing competition for TGF-β type-1 receptor (TβRI), blocking phosphorylation and activation of SMAD2. Moreover, SMAD7 recruits E3 ubiquitin SMURF ligases to the type I receptor to promote ubiquitin-mediated proteasomal degradation. In addition to its role in TGF-β and BMP signaling, SMAD7 is regulated by and implicated in a variety of other signaling pathways and functions as a mediator of crosstalk. This review is focused on SMAD7, its function in TGF-β and BMP signaling, and its role as a downstream integrator and crosstalk mediator. This crucial signaling molecule is tightly regulated by various mechanisms. We provide an overview of the ways by which SMAD7 is regulated, including noncoding RNAs (ncRNAs) and post-translational modifications (PTMs). Finally, we discuss its role in diseases, such as cancer, fibrosis, and inflammatory bowel disease (IBD).

摘要

转化生长因子 β (TGF-β) 家族成员在协调早期发育和成体组织稳态的细胞通讯中发挥着广泛的作用。异常的 TGF-β 家族信号传导与许多疾病的病理结果相关，深入了解分子和细胞过程可以为患者带来治疗益处。典型的 TGF-β 信号传导由受体调节的 SMADs (R-SMADs)、单一共介质 SMADs (Co-SMADs) 和抑制性 SMADs (I-SMADs) 介导。SMAD7 是 I-SMAD 之一，是多效性 TGF-β 和骨形态发生蛋白 (BMP) 信号通路的重要负调节因子。在负反馈回路中，SMAD7 通过提供 TGF-β 1 型受体 (TβRI) 的竞争来抑制 TGF-β 信号传导，阻断 SMAD2 的磷酸化和激活。而且，SMAD7 将 E3 泛素 SMURF 连接酶募集到 I 型受体以促进泛素介导的蛋白酶体降解。除了在 TGF-β 和 BMP 信号传导中的作用外，SMAD7 还受多种其他信号通路的调控并参与其中，并作为串扰的介质发挥作用。本综述的重点是 SMAD7、它在 TGF-β 和 BMP 信号传导中的功能，以及它作为下游积分器和串扰介质的作用。这种关键的信号分子受到各种机制的严格调控。我们概述了调节 SMAD7 的方式，包括非编码 RNA (ncRNA) 和翻译后修饰 (PTM)。最后，我们讨论了它在癌症、纤维化和炎症性肠病 (IBD) 等疾病中的作用。