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FADD death effector domain

PDB rendering based on 1a1w.
Available structures
1a1w, 1a1z, 1e3y, 1e41, 2gf5
Symbols FADD; GIG3; MGC8528; MORT1
External IDs OMIM602457 MGI109324 HomoloGene2836 GeneCards: FADD Gene
RNA expression pattern
PBB GE FADD 202535 at tn.png
More reference expression data
Species Human Mouse
Entrez 8772 14082
Ensembl ENSG00000168040 ENSMUSG00000031077
UniProt Q13158 Q8CD57
RefSeq (mRNA) NM_003824 NM_010175
RefSeq (protein) NP_003815 NP_034305
Location (UCSC) Chr 11:
69.73 - 69.73 Mb
Chr 7:
144.39 - 144.39 Mb
PubMed search [1] [2]
This article is about molecular biology. For other uses, see Fadd (disambiguation).

Fas-Associated protein with Death Domain (FADD) is an adaptor molecule that bridges the Fas-receptor, and other death receptors, to caspase-8 through its death domain to form the death inducing signaling complex (DISC) during apoptosis. The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be recruited by TNFRSF6/Fas-receptor, tumor necrosis factor receptor, TNFRSF25, and TNFSF10/TRAIL-receptor, and thus it participates in the death signaling initiated by these receptors. Interaction of this protein with the receptors unmasks the N-terminal effector domain[1](see structural image on the right side) of this protein, which allows it to recruit caspase-8, and thereby activate the cysteine protease cascade. Knockout studies in mice also suggest the importance of this protein in early T cell development.[2]

Signaling pathway of TNF-R1. Dashed grey lines represent multiple steps



FADD has been shown to interact with ABCA1,[3] CFLAR,[4][5][6] PEA15,[7][8] NACA,[9] Caspase 10,[10][11][5][12] Caspase 8,[10][13][5][14][15][16][17] Fas receptor,[10][18][19][20][21][17] Fas ligand,[10][13] DAP3,[22] DEDD,[23][24] TNFRSF1A,[10][25] TRADD,[14][25][17] TNFRSF10B[10][26] and MBD4.[27]

Overview of signal transduction pathways involved in apoptosis.


  1. ^ Eberstadt M, et al. (1998). "NMR structure and mutagenesis of the FADD (Mort1) death-effector domain". Nature 391: 941–5. doi:10.1038/31972.  
  2. ^ "Entrez Gene: FADD Fas (TNFRSF6)-associated via death domain".  
  3. ^ Buechler, Christa; Bared Salim Maa, Aslanidis Charalampos, Ritter Mirko, Drobnik Wolfgang, Schmitz Gerd (Nov. 2002). "Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein". J. Biol. Chem. (United States) 277 (44): 41307–10. doi:10.1074/jbc.C200436200. ISSN 0021-9258. PMID 12235128.  
  4. ^ Shu, H B; Halpin D R, Goeddel D V (Jun. 1997). "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity (UNITED STATES) 6 (6): 751–63. ISSN 1074-7613. PMID 9208847.  
  5. ^ a b c Srinivasula, S M; Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce C M, Litwack G, Tomaselli K J, Armstrong R C, Alnemri E S (Jul. 1997). "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis". J. Biol. Chem. (UNITED STATES) 272 (30): 18542–5. ISSN 0021-9258. PMID 9228018.  
  6. ^ Han, D K; Chaudhary P M, Wright M E, Friedman C, Trask B J, Riedel R T, Baskin D G, Schwartz S M, Hood L (Oct. 1997). "MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 94 (21): 11333–8. ISSN 0027-8424. PMID 9326610.  
  7. ^ Kitsberg, D; Formstecher E, Fauquet M, Kubes M, Cordier J, Canton B, Pan G, Rolli M, Glowinski J, Chneiweiss H (Oct. 1999). "Knock-out of the neural death effector domain protein PEA-15 demonstrates that its expression protects astrocytes from TNFalpha-induced apoptosis". J. Neurosci. (UNITED STATES) 19 (19): 8244–51. PMID 10493725.  
  8. ^ Condorelli, G; Vigliotta G, Cafieri A, Trencia A, Andalò P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F (Aug. 1999). "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis". Oncogene (ENGLAND) 18 (31): 4409–15. doi:10.1038/sj.onc.1202831. ISSN 0950-9232. PMID 10442631.  
  9. ^ Stilo, Romania; Liguoro Domenico, di Jeso Bruno, Leonardi Antonio, Vito Pasquale (Apr. 2003). "The alpha-chain of the nascent polypeptide-associated complex binds to and regulates FADD function". Biochem. Biophys. Res. Commun. (United States) 303 (4): 1034–41. ISSN 0006-291X. PMID 12684039.  
  10. ^ a b c d e f Gajate, Consuelo; Mollinedo Faustino (Mar. 2005). "Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy". J. Biol. Chem. (United States) 280 (12): 11641–7. doi:10.1074/jbc.M411781200. ISSN 0021-9258. PMID 15659383.  
  11. ^ Vincenz, C; Dixit V M (Mar. 1997). "Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling". J. Biol. Chem. (UNITED STATES) 272 (10): 6578–83. ISSN 0021-9258. PMID 9045686.  
  12. ^ Wang, J; Chun H J, Wong W, Spencer D M, Lenardo M J (Nov. 2001). "Caspase-10 is an initiator caspase in death receptor signaling". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (24): 13884–8. doi:10.1073/pnas.241358198. ISSN 0027-8424. PMID 11717445.  
  13. ^ a b Micheau, Olivier; Tschopp Jürg (Jul. 2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell (United States) 114 (2): 181–90. ISSN 0092-8674. PMID 12887914.  
  14. ^ a b Henshall, David C; Araki Tomohiro, Schindler Clara K, Shinoda Sachiko, Lan Jing-Quan, Simon Roger P (Sep. 2003). "Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures". J. Neurochem. (England) 86 (5): 1260–70. ISSN 0022-3042. PMID 12911633.  
  15. ^ Boldin, M P; Goncharov T M, Goltsev Y V, Wallach D (Jun. 1996). "Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death". Cell (UNITED STATES) 85 (6): 803–15. ISSN 0092-8674. PMID 8681376.  
  16. ^ Oshima, Shigeru; Turer Emre E, Callahan Joseph A, Chai Sophia, Advincula Rommel, Barrera Julio, Shifrin Nataliya, Lee Bettina, Benedict Yen T S, Yen Benjamin, Woo Tammy, Malynn Barbara A, Ma Averil (Feb. 2009). "ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development". Nature (England) 457 (7231): 906–9. doi:10.1038/nature07575. PMID 19060883.  
  17. ^ a b c Thomas, Lance R; Stillman David J, Thorburn Andrew (Sep. 2002). "Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen". J. Biol. Chem. (United States) 277 (37): 34343–8. doi:10.1074/jbc.M204169200. ISSN 0021-9258. PMID 12107169.  
  18. ^ MacFarlane, M; Ahmad M, Srinivasula S M, Fernandes-Alnemri T, Cohen G M, Alnemri E S (Oct. 1997). "Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL". J. Biol. Chem. (UNITED STATES) 272 (41): 25417–20. ISSN 0021-9258. PMID 9325248.  
  19. ^ Pan, G; O'Rourke K, Chinnaiyan A M, Gentz R, Ebner R, Ni J, Dixit V M (Apr. 1997). "The receptor for the cytotoxic ligand TRAIL". Science (UNITED STATES) 276 (5309): 111–3. ISSN 0036-8075. PMID 9082980.  
  20. ^ Huang, B; Eberstadt M, Olejniczak E T, Meadows R P, Fesik S W. "NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain". Nature (ENGLAND) 384 (6610): 638–41. doi:10.1038/384638a0. ISSN 0028-0836. PMID 8967952.  
  21. ^ Chinnaiyan, A M; O'Rourke K, Tewari M, Dixit V M (May. 1995). "FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis". Cell (UNITED STATES) 81 (4): 505–12. ISSN 0092-8674. PMID 7538907.  
  22. ^ Miyazaki, T; Reed J C (Jun. 2001). "A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins". Nat. Immunol. (United States) 2 (6): 493–500. doi:10.1038/88684. ISSN 1529-2908. PMID 11753396.  
  23. ^ Roth, Wilfried; Stenner-Liewen Frank, Pawlowski Krzysztof, Godzik Adam, Reed John C (Mar. 2002). "Identification and characterization of DEDD2, a death effector domain-containing protein". J. Biol. Chem. (United States) 277 (9): 7501–8. doi:10.1074/jbc.M110749200. ISSN 0021-9258. PMID 11741985.  
  24. ^ Stegh, A H; Schickling O, Ehret A, Scaffidi C, Peterhänsel C, Hofmann T G, Grummt I, Krammer P H, Peter M E (Oct. 1998). "DEDD, a novel death effector domain-containing protein, targeted to the nucleolus". EMBO J. (ENGLAND) 17 (20): 5974–86. doi:10.1093/emboj/17.20.5974. ISSN 0261-4189. PMID 9774341.  
  25. ^ a b Hsu, H; Shu H B, Pan M G, Goeddel D V (Jan. 1996). "TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways". Cell (UNITED STATES) 84 (2): 299–308. ISSN 0092-8674. PMID 8565075.  
  26. ^ Chaudhary, P M; Eby M, Jasmin A, Bookwalter A, Murray J, Hood L (Dec. 1997). "Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway". Immunity (UNITED STATES) 7 (6): 821–30. ISSN 1074-7613. PMID 9430227.  
  27. ^ Screaton, Robert A; Kiessling Stephan, Sansom Owen J, Millar Catherine B, Maddison Kathryn, Bird Adrian, Clarke Alan R, Frisch Steven M (Apr. 2003). "Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis". Proc. Natl. Acad. Sci. U.S.A. (United States) 100 (9): 5211–6. doi:10.1073/pnas.0431215100. ISSN 0027-8424. PMID 12702765.  

Further reading

  • Sheikh MS, Huang Y (2004). "The FADD is going nuclear.". Cell Cycle 2 (4): 346–7. PMID 12851487.  
  • Bhojani MS, Chen G, Ross BD, et al. (2007). "Nuclear localized phosphorylated FADD induces cell proliferation and is associated with aggressive lung cancer.". Cell Cycle 4 (11): 1478–81. PMID 16258269.  

See also

External links



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