Nonapoptotic functions of FADD-binding death receptors and their signaling molecules
Introduction
TNF-RI, the founding member of the death receptor (DR) family, has been known to have pleiotropic functions and therefore to activate multiple signaling pathways. This review will focus on non-apoptotic activities of CD95 (Fas) and the TRAIL receptors DR4 (TRAIL receptor 1/TR1) and DR5 (TRAIL receptor 2/TR2), three DR family members that have mostly been associated with induction of apoptosis. For information on non-apoptotic activities of TNFR-1, we refer the reader to a number of excellent and previously published reviews [1, 2, 3].
The key characteristic of all DRs is a conserved stretch of 80 amino acids in the cytoplasmic tail, the death domain (DD), that is required for apoptosis initiation. A shared property of CD95 and the DR4 and DR5 receptors is their ability to recruit FADD (Fas-interacting DD) through direct binding to their respective DDs [4]. We will therefore refer to this group of receptors as FADD-binding DRs (FBDRs). It is well established that FBDRs mediate apoptosis when triggered by their cognate membrane-bound or soluble ligand. Ligand binding induces the recruitment of FADD, procaspases 8 and 10, and the caspase-8/10 regulator c-FLIP to the receptor's DD, forming the death-inducing signaling complex (DISC) [5]. Active caspase-8 is then released into the cytosol leading to subsequent cleavage of the effector caspases 3 and 7. Receptor stimulation activates apoptosis through two distinct pathways that are either dependent on (Type II) or independent of (Type I) the mitochondrial amplification pathway [6]. Both CD95L and TRAIL have been reported to induce apoptosis through these two pathways [6].
It is likely that the nonapoptotic signaling of FBDRs described in this review occurs to some extent in all cells upon FBDR ligation. However, in cells that undergo apoptosis in response to ligation of these receptors, clearly the signaling through caspase-8 to caspase-3 predominates. The factors that determine which of the opposing responses predominate are currently unknown in most cases. However, in experimental systems where it has been examined, blocking of apoptosis makes it possible to study the other signaling responses to these receptors.
Section snippets
Non-apoptotic activities of FADD-binding death receptors
Originally identified as a death-inducing surface molecule in 1989, the biological function of CD95 was revealed by the phenotypes observed in the immune system of mice with lymphoproliferative (lpr) and generalized lymphoproliferative disease (gld) mutations, caused by defective expression of CD95 or CD95 ligand (CD95L), respectively [7]. These mouse mutant strains both exhibit lymphoproliferative disease, supporting the idea that the CD95–CD95L system has a major physiological role in the
Non-apoptotic signaling pathways of FADD-binding death receptors
All members of the DR family are known to activate multiple signaling pathways. Although the activation of ERK has been reported to be involved in CD95-stimulated growth in tumor cells [18], the proliferative signals of CD95 are poorly understood. CD95-dependent activation of ERK was also shown to induce neurite outgrowth in sensory neurons, which was associated with accelerated recovery from nerve injury in vivo [10•]. NF-κB activation by CD95 has been clearly linked to expression of
FADD
In addition to its established role as a DISC component and a mediator of the canonical apoptosis pathway, FADD has been implicated in multiple other functions. FADD has recently been shown to be involved in the autophagic death of IFNγ-treated HeLa cells through direct interaction with ATG5 [44]. Furthermore, FADD was shown to modulate IL-1R1–Toll receptor 4 signaling by binding to the adaptor protein MyD88. CD95 ligation was shown to enhance LPS- and IL-1β-induced NF-κB activation in
A novel DR-independent complex of the DISC components that regulates cell cycle progression
Since FADD's apoptotic function in cells is to recruit other DED-containing proteins, it is tempting to speculate that FADD is a major component of a novel complex containing DED proteins that regulate cell cycle progression. The nature and composition of a novel FADD-containing complex, its localization in the cell, and its functions are currently unknown; however, there are a number of findings that support the existence of this novel complex. In contrast to DR-deficient mice, mice deficient
Conclusions
Our understanding of how DRs mediate apoptosis has grown tremendously over the last ten years and so has the number of diseases in which too much or too little apoptosis is thought to contribute to pathology. DRs and their apoptosis signaling pathways have therefore been portrayed as promising targets for disease intervention. Although promotion or inhibition of DR-induced apoptosis may eventually lead to viable treatment strategies, it is imperative that we first understand all the activities
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to apologize to all the colleagues whose work could not be cited due to space limitations. Support to ME Peter has been provided by the National Institute of Health grants GM61712 and CA95319. R Schickel is supported by the Department of Defense fellowship DAMD17-03-1-0200.
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