Apoptosis Database

Description [+]

Synonyms: FADD, FAS (TNFRSF6)-ASSOCIATED VIA DEATH DOMAIN
Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Pisces; Danio rerio
Short gene description: Fas (tnfrsf6)-associated via death domain [Source:RefSeq_peptide;Acc:XP_001923893]
Family: Death Effector Domain-containing protein : DED adapter protein
Process: apoptosis,
Pathways: extrinsic pathway,
Criteria: manually curated
Curator comment: Ectopic expression of Casp8 in zebrafish embryos and human cell lines induces apoptosis [16888647]. Knockdown of FADD using antisense morpholino oligonucleotides protects zebrafish embryos from apoptosis induced by ectopic expression of Apo2L/TRAIL orthologs [16888647]. Zebrafish FADD directly associates with Casp8 through homophilic death effector domain (DED) interactions [17459614].
Human ortholog(s): FADD
WIKI: FADD-D_rerio

References [+]

Delineation of the cell-extrinsic apoptosis pathway in the zebrafish.
Eimon PM, Kratz E, Varfolomeev E, Hymowitz SG, Stern H, Zha J, Ashkenazi A
The mammalian extrinsic apoptosis pathway is triggered by Fas ligand (FasL) and Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL). Ligand binding to cognate receptors activates initiator caspases directly in a death-inducing signaling complex. In Drosophila, TNF ligand binding activates initiator caspases indirectly, through JNK. We characterized the extrinsic pathway in zebrafish to determine how it operates in a nonmammalian vertebrate. We identified homologs of FasL and Apo2L/TRAIL, their receptors, and other components of the cell death machinery. Studies with three Apo2L/TRAIL homologs demonstrated that they bind the receptors zHDR (previously linked to hematopoiesis) and ovarian TNFR (zOTR). Ectopic expression of these ligands during embryogenesis induced apoptosis in erythroblasts and notochord cells. Inhibition of zHDR, zOTR, the adaptor zFADD, or caspase-8-like proteases blocked ligand-induced apoptosis, as did antiapoptotic Bcl-2 family members. Thus, the extrinsic apoptosis pathway in zebrafish closely resembles its mammalian counterpart and cooperates with the intrinsic pathway to trigger tissue-specific apoptosis during embryogenesis in response to ectopic Apo2L/TRAIL expression. Cell Death Differ. 2006 Oct;13(10):1619-30. Epub 2006 Aug 4.

Conserved function of caspase-8 in apoptosis during bony fish evolution.
Sakata S,Yan Y,Satou Y,Momoi A,Ngo-Hazelett P,Nozaki M,Furutani-Seiki M,Postlethwait JH,Yonehara S,Sakamaki K
Caspase-8, a member of the caspase family, plays an important role in apoptotic signal transduction in mammals. Here we report the identification and characterization of the caspase-8 (casp8) gene in the zebrafish Danio rerio. The zebrafish casp8 gene has a genomic organization similar to mammalian casp8 genes, consisting of 10 exons. By chromosome mapping, we found that casp8 maps on linkage group 6 (LG6), a zebrafish chromosome segment orthologous to the long arm of human Chr. 2, which carries CASP8. In contrast, the zebrafish casp10-like gene and the cflar gene separately localize on LG9 and LG11, respectively, and these genes form a cluster with CASP8 on the human chromosome. This chromosomal segregation is unique to fish but not other vertebrates. Furthermore, we examined the function of zebrafish Casp8 protein in mammalian cells, and showed that it has pro-apoptotic activity when overexpressed. In addition, this molecule was capable of transmitting apoptotic signals mediated through not only Fas but also the TNF receptor in mouse Casp8-deficient cells. Expression analysis showed that casp8 is maternally expressed, and transcripts continue to be present throughout embryogenesis and into larval stages. These results show that zebrafish casp8 has a structure and function similar to mammalian CASP8 orthologs, and our study suggests that the role of caspase-8 in the apoptotic signal pathway has been conserved over at least 450 million years of vertebrate evolution. Gene. 2007 Jul 1;396(1):134-48. Epub 2007 Mar 27.

References from Human ortholog(s):

FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM
Using the cytoplasmic domain of Fas in the yeast two-hybrid system, we have identified a novel interacting protein, FADD, which binds Fas and Fas-FD5, a mutant of Fas possessing enhanced killing activity, but not the functionally inactive mutants Fas-LPR and Fas-FD8. FADD contains a death domain homologous to the death domains of Fas and TNFR-1. A point mutation in FADD, analogous to the lpr mutation of Fas, abolishes its ability to bind Fas, suggesting a death domain to death domain interaction. Overexpression of FADD in MCF7 and BJAB cells induces apoptosis, which, like Fas-induced apoptosis, is blocked by CrmA, a specific inhibitor of the interleukin-1 beta-converting enzyme. These findings suggest that FADD may play an important role in the proximal signal transduction of Fas. Cell. 1995 May 19;81(4):505-12.

Structure & Sequence [+]

Source	Domain Name	Start	End
PFAM A	DED	6	90
PFAM A	Death	106	189

Evolution [+]

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Homologs list [+]

Name	Relationship	Species
FADD	orthology	Chicken
FADD	orthology	Chimpanzee
FADD_BOVIN	orthology	Cow
FADD	orthology	Dog
FADD	orthology	Gasterosteus
FADD	orthology	Gorilla
FADD	orthology	Horse
FADD	orthology	Human
FADD	orthology	Lyzard
FADD	orthology	Macaca
Q56VD0_ORYLA	orthology	Medaka
FADD	orthology	Monodelphis
Fadd	orthology	Mouse
FADD	orthology	Orangutan
FADD	orthology	Ornithorhynchus
FADD	orthology	Rabbit
Fadd	orthology	Rat
FADD	orthology	Tetraodon
FADD	orthology	Xenopus
FADD	orthology	Zebra finch
CASP10	paralogy	Chicken
RIPK1	paralogy	Chimpanzee
RIPK1	paralogy	Dog
RIPK1	paralogy	Gorilla
RIPK1	paralogy	Human
CASP10	paralogy	Lyzard
RIPK1	paralogy	Macaca
RIPK1	paralogy	Monodelphis
RIPK1	paralogy	Orangutan
RIPK1	paralogy	Ornithorhynchus
RIPK1	paralogy	Rabbit
NP_001100820.1	paralogy	Rat
T_nigroviridis_ENSTNIP00000001216	paralogy	Tetraodon
casp10	paralogy	Xenopus
ANK1	paralogy	Xenopus
CASP10	paralogy	Zebra finch

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Gene Ontology [+]

GO id	Name	Ontology type	Evidence
GO:0007165	signal transduction	biological_proccess	IEA
GO:0042981	regulation of apoptosis	biological_proccess	IEA
GO:0005515	protein binding	mollecular_function	IEA

KEGG Pathways [+]

Information from other databases [+]

FADD (Danio rerio)