Lin Xia, Chen Yeguang, Meng Anming, Feng Xinhua
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston TX 77030, USA.
J Genet Genomics. 2007 Jan;34(1):1-9. doi: 10.1016/S1673-8527(07)60001-0.
The transforming growth factor-beta (TGF-beta) and related growth factors activate a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. They play key roles in the pathogenesis of many diseases especially cancer, fibrotic diseases, autoimmune diseases and cardiovascular diseases. TGF-beta receptor-mediated phosphorylation of R-SMADs represents the most critical step in the TGF-beta signaling pathways that triggers a cascade of intracellular events from SMAD complex assembly in the cytoplasm to transcriptional control in the nucleus. Conversely, dephosphorylation of R-SMADs is a key mechanism for terminating TGF-beta signaling. Our labs have recently taken an integrated approach combining functional genomics, biochemistry and development biology to describe the isolation and functional characterization of protein phosphatase PPM1A in controlling TGF-beta signaling. This article briefly reviews how dynamic phosphorylation and dephosphorylation of SMADs control or fine-tune the signaling strength and duration and ultimately the physiological consequences in TGF-beta signaling.
转化生长因子-β（TGF-β）及相关生长因子通过自分泌、旁分泌和内分泌方式在多细胞生物中激活广泛的细胞反应。它们在许多疾病尤其是癌症、纤维化疾病、自身免疫性疾病和心血管疾病的发病机制中起关键作用。TGF-β受体介导的R-SMAD磷酸化是TGF-β信号通路中最关键的步骤，该步骤触发了从细胞质中SMAD复合物组装到细胞核中转录控制的一系列细胞内事件。相反，R-SMAD的去磷酸化是终止TGF-β信号的关键机制。我们实验室最近采用了一种综合方法，结合功能基因组学、生物化学和发育生物学来描述蛋白磷酸酶PPM1A在控制TGF-β信号中的分离和功能特性。本文简要综述了SMAD的动态磷酸化和去磷酸化如何控制或微调信号强度和持续时间，以及最终在TGF-β信号中的生理后果。
