Trends in Immunology
ReviewFADD at the Crossroads between Cancer and Inflammation
Section snippets
FADD: Roles beyond Apoptosis
FADD is a nearly ubiquitous, well conserved across species, key adaptor protein transmitting apoptotic signals mediated by the DRs of the tumor necrosis factor (TNF) receptor (TNF-R) superfamily such as TNF-R1, FAS (CD95/APO-1), DR3, TRAIL (TNF-related apoptosis-inducing ligand)-R1 (DR4) and TRAIL-R2 (DR5) 1, 2, 3, 4. In all cell types, FADD can act as a bridge between these DRs and initiator pro-caspase-8/10, mediated by two highly conserved domains: the death domain (DD) and the death
FADDosome
Inflammation is a hallmark of numerous types of cancer, and many studies have highlighted a clear role for FADD in inflammation. A recent report described a FADDosome complex involved in regulating inflammation upon TRAIL stimulation [23]. Although engagement of TRAIL-R1 or -R2 by TRAIL could induce apoptosis through FADD recruitment and caspase-8 activation [4] (Figure 1A), it is suggested that TRAIL-R stimulation could also lead to nuclear factor (NF)-κB activation in human cell lines [23].
FADD: Putative Cancer Driver
Human FADD gene is located on chromosome 11q13.3, a region prone to amplification in several human malignancies including breast, lung, skin, esophagus, and head and neck cancers [48]. These amplification events have prompted the idea that an abnormal FADD gene might act as a potential cancer driver [48]. However, FADD gene amplification seems to be cancer-type specific as it is not found in human lung adenocarcinoma [49] but is reported in oral, esophageal, laryngeal, and breast carcinomas,
Regulation of FADD Protein by Phosphorylation: Implications in Cancer
Human FADD protein can be phosphorylated at serine 194 [15], 200 [55], and 203 [56] (Figure 3A), and several kinases/phosphatases regulating FADD phosphorylation have been described (Figure 3B and Box 2). FADD phosphorylation at Ser194, or at its homolog Ser191 in mice [16], is cell-cycle dependent and necessary for the G2/M transition, and therefore cell proliferation 15, 17, 57. This phosphorylation site also regulates FADD subcellular localization: Ser194 phosphorylated FADD (194P-FADD) is
Concluding Remarks
Collectively, these studies suggest that FADD plays a role in tumorigenesis, given that FADD gene overexpression is associated with tumor growth and poor prognosis in certain cancer patients 60, 61, 62. Nonetheless, FADD might also promote tumor suppression via its proapoptotic function [23]. The opposing roles of FADD in tumor development might be related to the opposing functions of FADD in inflammatory processes. Indeed, FADD is a key signaling molecule implicated in most signalosome
Glossary
- Adenosine receptors
- G protein-coupled receptors mediating the physiological actions of adenosine, and involved in many pathophysiological processes such as immune responses, inflammatory diseases, and cancer.
- Arginine GlcNAcylation
- atypical glycosylation of arginine residues mediated by bacterial glycosyltransferase enzymes not observed in eukaryotic cells.
- Autophagic cell death
- a form of regulated cell death that depends on the autophagic machinery.
- Cancer driver
- a gene whose amplification-driven
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