Discipline of Pharmacy, School of Medical Sciences and Diabetes Complications Group, Health Innovations Research Institute, RMIT University, Bundoora, VIC 3083 Australia.
Cell Signal. 2013 Oct;25(10):2017-24. doi: 10.1016/j.cellsig.2013.06.001. Epub 2013 Jun 11.
Transforming growth factor-β (TGF-β) is a secreted homodimeric protein that plays an important role in regulating various cellular responses including cell proliferation and differentiation, extracellular matrix production, embryonic development and apoptosis. Disruption of the TGF-β signalling pathway is associated with diverse disease states including cancer, renal and cardiac fibrosis and atherosclerosis. At the cell surface TGF-β complex consists of two type I and two type II transmembrane receptors (TβRI and TβRII respectively) which have serine/threonine kinase activity. Upon TGF-β engagement TβRII phosphorylates TβRI which in turn phosphorylates Smad2/3 on two serine residues at their C-terminus which enables binding to Smad4 to form heteromeric Smad complexes that enter the nucleus to initiate gene transcription including for extracellular matrix proteins. TGF-β signalling is also known to activate other serine/threonine kinase signalling that results in the phosphorylation of the linker region of Smad2. The Smad linker region is defined as the domain which lies between the MH1 and MH2 domains of a Smad protein. Serine/threonine kinases that are known to phosphorylate the Smad linker region include mitogen-activated protein kinases, extracellular-signal regulated kinase, Jun N-terminal kinase and p38 kinase, the tyrosine kinase Src, phosphatidylinositol 3'-kinase, cyclin-dependent kinases, rho-associated protein kinase, calcium calmodulin-dependent kinase and glycogen synthase kinase-3. This review will cover the role of Smad linker region phosphorylation downstream of TGF-β signalling in vascular cells. Key factors including the identification of the kinases that phosphorylate individual Smad residues, the upstream agents that activate these kinases, the cellular location of the phosphorylation event and the importance of the linker region in regulation and expression of genes induced by TGF-β are covered.
转化生长因子-β（TGF-β）是一种分泌的同源二聚体蛋白，在调节各种细胞反应中起着重要作用，包括细胞增殖和分化、细胞外基质产生、胚胎发育和细胞凋亡。TGF-β信号通路的破坏与多种疾病状态有关，包括癌症、肾和心脏纤维化以及动脉粥样硬化。在细胞表面，TGF-β复合物由两种类型 I 和两种类型 II 跨膜受体（分别为 TβRI 和 TβRII）组成，它们具有丝氨酸/苏氨酸激酶活性。TGF-β结合后，TβRII 磷酸化 TβRI，TβRI 又磷酸化 Smad2/3 的 C 端两个丝氨酸残基，使其与 Smad4 结合形成异源 Smad 复合物，进入细胞核启动基因转录，包括细胞外基质蛋白。TGF-β信号还已知激活其他丝氨酸/苏氨酸激酶信号，导致 Smad2 连接区的磷酸化。Smad 连接区被定义为 Smad 蛋白的 MH1 和 MH2 结构域之间的结构域。已知磷酸化 Smad 连接区的丝氨酸/苏氨酸激酶包括有丝分裂原激活的蛋白激酶、细胞外信号调节激酶、Jun N-末端激酶和 p38 激酶、酪氨酸激酶Src、磷脂酰肌醇 3'-激酶、细胞周期蛋白依赖性激酶、rho 相关蛋白激酶、钙调蛋白依赖性激酶和糖原合成酶激酶-3。这篇综述将涵盖 TGF-β信号下游 Smad 连接区磷酸化在血管细胞中的作用。涵盖的关键因素包括鉴定磷酸化单个 Smad 残基的激酶、激活这些激酶的上游因子、磷酸化事件的细胞位置以及连接区在 TGF-β诱导的基因表达和调控中的重要性。
