Caspase activation via extrinsic apoptotic signalling pathway

Caspases, a family of cysteine proteases, execute apoptotic cell death. Caspases exist as inactive zymogens in cells and undergo a cascade of catalytic activation at the onset of apoptosis. Initiation of apoptosis occurs through either a cell-intrinsic or cell-extrinsic pathway. Extrinsic pathway cell death signals originate at the plasma membrane where:<ul><li>An extracellular ligand (e.g., FasL) binds to its cell surface transmembrane “death receptor” (e.g., Fas receptor), inducing oligomerization of the receptor (Trauth et al. 1989; Itoh and Nagata 1993; Danial and Korsmeyer 2004). The "death receptors" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). Ligand binding promotes clustering of proteins that bind to the intracellular domain of the receptor (e.g., FADD, or Fas-associated death domain-containing protein), which then binds to the prodomain of initiator caspases (e.g.caspase-8 or -10) to promote their dimerization and activation. Active caspase-8/-10 can then directly cleave and activate effector caspases, such as caspase-3 or it can cleave Bid, which facilitates mitochondrial cytochrome c release.</li><li>Unique group of proteins termed dependence receptors (DpRs) transduce positive (often prosurvival or progrowth) signals when engaged by ligand, but emit proapoptotic signals in the absence of ligand (Goldschneider and Mehlen 2010). DpR family includes p75 neurotrophin receptor (p75NTR), deleted in colon cancer (DCC), and UNC5 homologs, among others. cell-surface membrane receptors.</li></ul>

Caspases，一种半胱氨酸蛋白酶家族，负责执行细胞凋亡过程。Caspases 在细胞内以无活性的前酶形式存在，并在细胞凋亡的起始阶段经历一系列的催化激活反应。凋亡的启动可通过细胞内或细胞外途径实现。细胞外途径的细胞死亡信号源于质膜，其中：<ul><li>细胞外配体（例如，FasL）与细胞表面的跨膜“死亡受体”（例如，Fas 受体）结合，诱导受体的寡聚化（Trauth 等，1989；Itoh 和 Nagata，1993；Danial 和 Korsmeyer，2004）。所谓的“死亡受体”是一类特殊的细胞表面受体，包括 Fas/CD95、肿瘤坏死因子-α（TNF-α）受体 1 以及与 TNF-α 相关的凋亡诱导配体（TRAIL）结合的两个受体，即 DR4 和 DR5。配体的结合促进与受体胞内域结合的蛋白质（例如，FADD 或 Fas 相关的死亡结构域蛋白）的聚集，随后这些蛋白质与启动型 Caspases 的前结构域（例如，caspase-8 或 -10）结合，以促进其二聚化和激活。活性 caspase-8/-10 可以直接切割并激活效应型 Caspases，如 caspase-3，或者切割 Bid，从而促进线粒体细胞色素 c 的释放。</li><li>称为依赖性受体（DpRs）的蛋白质独特群体，在配体结合时传递阳性（通常为促生存或促生长）信号，但在配体不存在时发出促凋亡信号（Goldschneider 和 Mehlen，2010）。DpR 家族包括 p75 神经生长因子受体（p75NTR）、结肠癌缺失（DCC）和 UNC5 同源物等，均为细胞表面膜受体。</li></ul>