Algeciras-Schimnich Alicia, Shen Le, Barnhart Bryan C, Murmann Andrea E, Burkhardt Janis K, Peter Marcus E
The Ben May Institute for Cancer Research. Department of Medicine. Department of Pathology University of Chicago, Chicago, Illinois 60637, USA.
Mol Cell Biol. 2002 Jan;22(1):207-20. doi: 10.1128/MCB.22.1.207-220.2002.
Binding of either ligand or agonistic antibodies to the death receptor CD95 (APO-1/Fas) induces the formation of the death-inducing signaling complex (DISC). We now show that signal initiation of CD95 in type I cells can be further separated into at least four distinct steps. (i) The first step is ligand-induced formation of CD95 microaggregates at the cell surface. (ii) The second step is recruitment of FADD to form a DISC. This step is dependent on actin filaments. (iii) The third step involves formation of large CD95 surface clusters. This event is positively regulated by DISC-generated caspase 8. (iv) The fourth step is internalization of activated CD95 through an endosomal pathway. The latter step is again dependent on the presence of actin filaments. The data indicate that the signal initiation by CD95 is a complex process actively regulated at various levels, providing a number of new drug targets to specifically modulate CD95 signaling.
配体或激动性抗体与死亡受体CD95（APO-1/Fas）结合会诱导死亡诱导信号复合物（DISC）的形成。我们现在表明，I型细胞中CD95的信号启动可进一步分为至少四个不同步骤。（i）第一步是配体诱导细胞表面形成CD95微聚集体。（ii）第二步是募集FADD以形成DISC。这一步依赖于肌动蛋白丝。（iii）第三步涉及形成大的CD95表面簇。这一事件受到DISC产生的半胱天冬酶8的正向调节。（iv）第四步是活化的CD95通过内体途径内化。后一步同样依赖于肌动蛋白丝的存在。数据表明，CD95的信号启动是一个在多个水平上受到积极调控的复杂过程，提供了许多新的药物靶点来特异性调节CD95信号传导。
