Principles and mechanisms of CD95 activation.

Abstract

CD95 (Apo1/Fas) has been originally identified as the target of cell death-inducing antibodies. The recognition of CD95 as an apoptosis-triggering receptor represents one of the early milestones in the apoptosis field. Moreover, the research on CD95-induced cell death fostered various other discoveries of broad and general relevance in cell biology, for example, the identification of caspase 8 as the initiator caspase of the extrinsic apoptosis pathway. Activation of CD95-associated intracellular signaling pathways is not a simple consequence of ligand binding but is the fine-tuned result of a complex interplay of various molecular mechanisms that eventually determine the strength and quality of the CD95 response. There is growing evidence that different forms of CD95 stimulation trigger the assembly of CD95 signaling complexes of distinct composition. Moreover, the formation of signaling competent CD95 complexes is a multistep process and the subject of regulation by various cellular cues. This review addresses the relevance of the molecular nature of the CD95-stimulating agonist for the quality of the CD95 response and discusses the importance of modification, clustering, internalization, and lipid raft and actin association of CD95 for CD95 activity.