Special Viewpoints

The Fas Signaling Pathway: More Than a Paradigm

See allHide authors and affiliations

Science  31 May 2002:
Vol. 296, Issue 5573, pp. 1635-1636
DOI: 10.1126/science.1071553


Apoptosis and related forms of cell death have central importance in development, homeostasis, tumor surveillance, and the function of the immune system. Apoptosis is initiated by two principal pathways. The intrinsic pathway emerges from mitochondria, whereas the extrinsic pathway is activated by the ligation of death receptors. This Viewpoint introduces the basic mechanisms of the extrinsic pathway, using the example of the prototypical death receptor Fas and its role in apoptosis, but it also points out the increasingly understood importance of this receptor as a non-apoptotic signal transducer.

Fas (also called Apo-1 or CD95) is a death domain–containing member of the tumor necrosis factor receptor (TNFR) superfamily. It has a central role in the physiological regulation of programmed cell death and has been implicated in the pathogenesis of various malignancies and diseases of the immune system (1, 2) [see Fas Signaling Pathway,http://stke.sciencemag.org/cgi/cm/CMP_7966 (3) and Fas Signaling Pathway in Cardiomyocytes,http://stke.sciencemag.org/cgi/cm/CMP_9993(4)]. Although the Fas ligand (FasL)–Fas system has been appreciated mainly with respect to its death-inducing function, it also transduces proliferative and activating signals through pathways that are still poorly defined (1,2).

In the absence of membrane-bound ligand, inactive complexes of Fas are formed by the pre–ligand-binding assembly domain of the molecule (2). Interaction with membrane-bound FasL (or agonistic antibodies) reorganizes these complexes and allows the formation of a death-inducing signaling complex (DISC). The Fas DISC contains the adaptor protein Fas-associated death domain protein (FADD) and caspases 8 and 10, which can initiate the process of apoptosis. FasL-induced clustering of Fas, FADD, and caspase-8 or -10 within the DISC results in autoproteolytic processing of these caspases by induced proximity and in release of the processed active proteases (Fig. 1). In type I cells, processed caspase-8 is sufficient to directly activate other members of the caspase family, whose action on defined substrates paves the way to the execution phase of apoptosis (1). In type II cells, proper activation of effector caspases by Fas depends on an amplification loop that relies on caspase-8–mediated cleavage of the pro-apoptotic Bcl-2 family member Bid and subsequent release of mitochondrial pro-apoptotic factors [for example, cytochrome c and second mitochondria-derived activator of caspases (SMAC, also called Diablo)] to drive the formation of the caspase-9–activating apoptosome. Active caspase-9 activates the executioner caspase-3, which in turn activates caspase-8 outside the Fas DISC, thereby completing a positive feedback loop (1).

Figure 1

Fas L-induced apoptosis occurs by autoproteolytical processing of caspase-8 (for details, see text).

Each step in Fas-mediated apoptosis can be a target of regulatory mechanisms enabling cells to show flexible responses to stimulation by Fas. Corresponding to the hierarchy of events in Fas-mediated apoptosis, these regulatory mechanisms can be specific for Fas or common to death receptors, or they can affect the apoptotic core machinery of the cell. The FasL gene is transcriptionally inactive in most cells. Thus, regulation of FasL expression itself, for example, by the transcription factors nuclear factor kappa B (NF-κB), activating protein 1 (AP1), or nuclear factor of activated T cells (NF-AT), regulates FasL/Fas-mediated effects, such as those of activation-induced cell death of CD4+ T cells (5). To a lesser extent, regulation of Fas expression is also used to control Fas responses, for example, in p53-induced apoptosis. Stimulation of Fas by membrane-bound FasL can be antagonized by the soluble decoy receptor DcR3, by various Fas isoforms lacking the transmembrane and/or death domains, and by soluble FasL generated by proteolytic processing or alternative splicing. The caspase-8–activating capacity of the Fas-DISC is mainly regulated by FADD-like interleukin-1β–converting enzyme (FLICE)–like inhibitory protein (FLIP) (6). FLIP exists in several isoforms that are structurally similar to caspase-8 although lacking in enzymatic activity (6). FLIP can be incorporated into the DISC of death receptors, thereby disabling DISC-mediated processing and release of active caspase-8 (6). In addition, Fas-mediated apoptosis is controlled by a plethora of regulators of the mitochondrial pathway of cell death, for example, by Bcl-2 family members, SMAC, or inhibitor of apoptosis proteins (1). Fas-mediated cell death occurs not only by apoptosis but also, depending on the cellular context, by necrosis. Fas-induced necrosis requires the adaptor protein FADD and the Fas-interacting serine/threonine kinase receptor-interacting protein (RIP), whereas caspase-8 seems to be dispensable (7). However, the molecular mechanisms linking Fas, FADD, and RIP to the execution processes of necrosis (for example, the production of reactive oxygen species) are not yet clear.

Although Fas is recognized predominantly as a death inducer, it also transduces proliferative signals in normal human diploid fibroblasts and T cells (2). The signaling pathways underlying Fas-induced proliferation might be partly related to the apoptotic pathway. In fact, stimulation of T cell growth by FasL can be blocked by caspase inhibitors. In addition, caspase-8, FADD, and FLIP are implicated in Fas-induced expression of the proto-oncogene c-fos, and mice deficient in these molecules have a defect in T cell proliferation. To what extent the Fas-mediated proliferation is related to activation of NF-κB, another non-apoptotic response elicited by Fas, remains to be clarified. A role of c-Jun NH2-terminal kinase (JNK) activation in Fas-mediated proliferation seems rather unlikely, because FADD is normally not required for the activation of JNK. Rather, Fas promotes JNK activation through interaction with the Fas-binding protein DAXX and apoptosis signal–regulated kinase 1 (Ask1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family. Although JNK activation often correlates with Fas-mediated apoptosis, the pro-apoptotic effect of JNK activation (for example, up-regulation of FasL) normally does not directly contribute to Fas-dependent cell death. Some recent studies point to a role of JNK activation in Fas-mediated cardiac hypertrophy that occurs in response to the stress of pressure overload in the absence of apoptosis (8).

Since the cloning of Fas in 1991, tremendous progress has been made in the understanding of the molecular basis of apoptosis induction by this receptor. Nevertheless, many facets of Fas function are still poorly understood, in particular with respect to its non-apoptotic functions. Thus, it is easy to predict that, for now, the FasL-Fas system will remain as a death receptor paradigm; however, research in the years to come should shed more light onto other, non-apoptotic functions of these prominent members of the TNF/TNFR family.


View Abstract

Stay Connected to Science

Navigate This Article