Signal Transduction Laboratory, School of Biochemistry and Cell Biology, Analytical and Biological Chemistry Research Facility (ABCRF), Western Gateway Building, University College Cork, Cork, Ireland.
Signal Transduction Laboratory, School of Biochemistry and Cell Biology, Analytical and Biological Chemistry Research Facility (ABCRF), Western Gateway Building, University College Cork, Cork, Ireland
Biochem Soc Trans. 2017 Dec 15;45(6):1185-1202. doi: 10.1042/BST20170002. Epub 2017 Oct 27.
Receptor signalling events including those initiated following activation of cytokine and growth factor receptors and the well-characterised death receptors (tumour necrosis factor receptor, type 1, FasR and TRAIL-R1/2) are initiated at the cell surface through the recruitment and formation of intracellular multiprotein signalling complexes that activate divergent signalling pathways. Over the past decade, research studies reveal that many of these receptor-initiated signalling events involve the sequential proteolysis of specific receptors by membrane-bound proteases and the γ-secretase protease complexes. Proteolysis enables the liberation of soluble receptor ectodomains and the generation of intracellular receptor cytoplasmic domain fragments. The combined and sequential enzymatic activity has been defined as regulated intramembrane proteolysis and is now a fundamental signal transduction process involved in the termination or propagation of receptor signalling events. In this review, we discuss emerging evidence for a role of the γ-secretase protease complexes and regulated intramembrane proteolysis in cell- and immune-signalling pathways.
受体信号事件，包括细胞因子和生长因子受体激活后引发的以及特征明确的死亡受体（肿瘤坏死因子受体 1 型、FasR 和 TRAIL-R1/2）引发的，都是通过细胞表面募集和形成细胞内多蛋白信号复合物来启动的，这些复合物可以激活不同的信号通路。在过去的十年中，研究表明，许多这些受体引发的信号事件都涉及到特定受体的膜结合蛋白酶和γ-分泌酶蛋白酶复合物的顺序蛋白水解。蛋白水解使可溶性受体细胞外结构域释放，并产生细胞内受体细胞质结构域片段。这种联合和顺序的酶活性被定义为调控的跨膜蛋白水解，现在是参与受体信号事件终止或传播的基本信号转导过程。在这篇综述中，我们讨论了 γ-分泌酶蛋白酶复合物和调控的跨膜蛋白水解在细胞和免疫信号通路中的作用的新证据。
