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Gene Review

FADD  -  Fas (TNFRSF6)-associated via death domain

Homo sapiens

Synonyms: FAS-associated death domain protein, FAS-associating death domain-containing protein, GIG3, Growth-inhibiting gene 3 protein, MORT1, ...
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Disease relevance of FADD

  • In an in vivo FHF model, the Fas-associated death domain (FADD), adenovirus selectively blocked the intracellular pathway, leading to mitochondrial cytochrome c release, caspase-3 activation, and, thus, apoptosis of hepatocytes [1].
  • The FADD-binding region of MBD4 was downstream of a frameshift mutation that occurs in a significant fraction of human colorectal carcinomas [2].
  • Recombinant expression of a dominant negative form of FADD or the C terminus of ABCA1 in the human hepatoma cell line HepG2 markedly reduced the transfer of phospholipids to apoA-I [3].
  • In this study we investigated death receptors, FAS-associated death domain protein (FADD), the activation of caspases-10 and -8 as well as the downstream caspases, and reactive oxygen species (ROS) in taxol-induced apoptosis in the CCRF-HSB-2 human lymphoblastic leukemia cell line [4].
  • These findings suggest that the FADD gene is a novel and useful tool for the treatment of malignant gliomas [5].
  • Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser(194) phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival [6].

Psychiatry related information on FADD

  • The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed [7].

High impact information on FADD


Chemical compound and disease context of FADD


Biological context of FADD

  • Fas-associated death domain protein (FADD) is an adaptor protein bridging death receptors with initiator caspases [2].
  • The nuclear localization of FADD and its interaction with a genome surveillance/DNA repair protein that can regulate apoptosis suggests a novel function of FADD distinct from direct participation in death receptor signaling complexes [2].
  • This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm [15].
  • The phosphorylation of FADD was found to correlate with the cell cycle [16].
  • These results were confirmed by transient transfection of constructs encoding either a FADD dominant negative mutant or MC159 or E8 viral proteins that inhibit the FADD/caspase-8 pathway [17].

Anatomical context of FADD

  • Studies in this animal model indicate that FADD may serve as a molecular target to prevent liver cell death in vivo [1].
  • The impact of FADD/MORT1-transduced signals on T lymphocyte development was investigated in transgenic mice expressing a dominant negative mutant protein, FADD-DN [18].
  • Surprisingly, the data presented here demonstrate that FADD is mainly nuclear in several adherent cell lines [2].
  • Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking [19].
  • Moreover, the ability of death receptors to induce NF-kappaB activation was drastically reduced in a FADD-deficient Jurkat cell line [20].

Associations of FADD with chemical compounds


Physical interactions of FADD

  • FAF1 could interact with caspase-8 and FADD in vivo as well as in vitro [23].
  • Fas-associated death domain protein (FADD) was identified to bind to ABCA1, and this interaction was confirmed by pull-down assays and co-immunoprecipitations [3].
  • We show that the pro-domain of FLICE2 encodes a functional death effector domain that binds to the corresponding domain in the adapter molecule FADD [24].
  • Using this method, we identified mutations in FADD that prevent binding to Fas but do not affect binding to TRADD [25].
  • By employing FADD-deficient Jurkat cells, we demonstrate that DR5 and c-FLIP(L) interact in a FADD-independent manner [26].

Enzymatic interactions of FADD


Co-localisations of FADD


Regulatory relationships of FADD


Other interactions of FADD

  • TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB [33].
  • We have also found that binding of DAP3 to FADD and activation of pro-caspase-8 in an in vitro reconstituted system is GTP-dependent [34].
  • This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA [35].
  • These results indicate that IFNgamma acts on ECFC not only to upregulate Fas, but also to selectively upregulate caspases-1, -3, and -8, which are activated and produce apoptosis, whereas the concentrations of FasL and FADD are not demonstrably changed [36].
  • Usurpin heterodimerized with pro-caspase-8 in vitro and precluded pro-caspase-8 recruitment by the FADD/MORT1 adapter protein [37].

Analytical, diagnostic and therapeutic context of FADD


  1. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Streetz, K., Leifeld, L., Grundmann, D., Ramakers, J., Eckert, K., Spengler, U., Brenner, D., Manns, M., Trautwein, C. Gastroenterology (2000) [Pubmed]
  2. Fas-associated death domain protein interacts with methyl-CpG binding domain protein 4: a potential link between genome surveillance and apoptosis. Screaton, R.A., Kiessling, S., Sansom, O.J., Millar, C.B., Maddison, K., Bird, A., Clarke, A.R., Frisch, S.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. Molecular and functional interaction of the ATP-binding cassette transporter A1 with Fas-associated death domain protein. Buechler, C., Bared, S.M., Aslanidis, C., Ritter, M., Drobnik, W., Schmitz, G. J. Biol. Chem. (2002) [Pubmed]
  4. Taxol induces caspase-10-dependent apoptosis. Park, S.J., Wu, C.H., Gordon, J.D., Zhong, X., Emami, A., Safa, A.R. J. Biol. Chem. (2004) [Pubmed]
  5. FADD gene therapy for malignant gliomas in vitro and in vivo. Kondo, S., Ishizaka, Y., Okada, T., Kondo, Y., Hitomi, M., Tanaka, Y., Haqqi, T., Barnett, G.H., Barna, B.P. Hum. Gene Ther. (1998) [Pubmed]
  6. Amplicon mapping and expression profiling identify the Fas-associated death domain gene as a new driver in the 11q13.3 amplicon in laryngeal/pharyngeal cancer. Gibcus, J.H., Menkema, L., Mastik, M.F., Hermsen, M.A., de Bock, G.H., van Velthuysen, M.L., Takes, R.P., Kok, K., Alvarez Marcos, C.A., van der Laan, B.F., van den Brekel, M.W., Langendijk, J.A., Kluin, P.M., van der Wal, J.E., Schuuring, E. Clin. Cancer Res. (2007) [Pubmed]
  7. Signaling for survival and apoptosis in the immune system. Mak, T.W., Yeh, W.C. Arthritis Res. (2002) [Pubmed]
  8. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Micheau, O., Tschopp, J. Cell (2003) [Pubmed]
  9. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Boldin, M.P., Goncharov, T.M., Goltsev, Y.V., Wallach, D. Cell (1996) [Pubmed]
  10. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Liu, Z.G., Hsu, H., Goeddel, D.V., Karin, M. Cell (1996) [Pubmed]
  11. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death--inducing signaling complex. Muzio, M., Chinnaiyan, A.M., Kischkel, F.C., O'Rourke, K., Shevchenko, A., Ni, J., Scaffidi, C., Bretz, J.D., Zhang, M., Gentz, R., Mann, M., Krammer, P.H., Peter, M.E., Dixit, V.M. Cell (1996) [Pubmed]
  12. FADD phosphorylation is critical for cell cycle regulation in breast cancer cells. Matsuyoshi, S., Shimada, K., Nakamura, M., Ishida, E., Konishi, N. Br. J. Cancer (2006) [Pubmed]
  13. Phosphorylation status of Fas-associated death domain-containing protein (FADD) is associated with prostate cancer progression. Shimada, K., Matsuyoshi, S., Nakamura, M., Ishida, E., Konishi, N. J. Pathol. (2005) [Pubmed]
  14. STAT-1-independent upregulation of FADD and procaspase-3 and -8 in cancer cells treated with cytotoxic drugs. Micheau, O., Hammann, A., Solary, E., Dimanche-Boitrel, M.T. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  15. The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. Bender, L.M., Morgan, M.J., Thomas, L.R., Liu, Z.G., Thorburn, A. Cell Death Differ. (2005) [Pubmed]
  16. Phosphorylation of FADD/ MORT1 at serine 194 and association with a 70-kDa cell cycle-regulated protein kinase. Scaffidi, C., Volkland, J., Blomberg, I., Hoffmann, I., Krammer, P.H., Peter, M.E. J. Immunol. (2000) [Pubmed]
  17. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. Micheau, O., Solary, E., Hammann, A., Dimanche-Boitrel, M.T. J. Biol. Chem. (1999) [Pubmed]
  18. A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. Newton, K., Harris, A.W., Bath, M.L., Smith, K.G., Strasser, A. EMBO J. (1998) [Pubmed]
  19. Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia. Martin, D.A., Zheng, L., Siegel, R.M., Huang, B., Fisher, G.H., Wang, J., Jackson, C.E., Puck, J.M., Dale, J., Straus, S.E., Peter, M.E., Krammer, P.H., Fesik, S., Lenardo, M.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  20. Inhibition of death receptor-mediated gene induction by a cycloheximide-sensitive factor occurs at the level of or upstream of Fas-associated death domain protein (FADD). Wajant, H., Haas, E., Schwenzer, R., Muhlenbeck, F., Kreuz, S., Schubert, G., Grell, M., Smith, C., Scheurich, P. J. Biol. Chem. (2000) [Pubmed]
  21. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. Herr, I., Wilhelm, D., Böhler, T., Angel, P., Debatin, K.M. EMBO J. (1997) [Pubmed]
  22. Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Beltinger, C., Fulda, S., Kammertoens, T., Meyer, E., Uckert, W., Debatin, K.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  23. Fas-associated factor 1, FAF1, is a member of Fas death-inducing signaling complex. Ryu, S.W., Lee, S.J., Park, M.Y., Jun, J.I., Jung, Y.K., Kim, E. J. Biol. Chem. (2003) [Pubmed]
  24. 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. Vincenz, C., Dixit, V.M. J. Biol. Chem. (1997) [Pubmed]
  25. Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen. Thomas, L.R., Stillman, D.J., Thorburn, A. J. Biol. Chem. (2002) [Pubmed]
  26. Fas-associated protein with death domain (FADD)-independent recruitment of c-FLIPL to death receptor 5. Jin, T.G., Kurakin, A., Benhaga, N., Abe, K., Mohseni, M., Sandra, F., Song, K., Kay, B.K., Khosravi-Far, R. J. Biol. Chem. (2004) [Pubmed]
  27. Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells. Li, Y., Mao, Y., Rosal, R.V., Dinnen, R.D., Williams, A.C., Brandt-Rauf, P.W., Fine, R.L. Int. J. Cancer (2005) [Pubmed]
  28. JNK regulates HIPK3 expression and promotes resistance to Fas-mediated apoptosis in DU 145 prostate carcinoma cells. Curtin, J.F., Cotter, T.G. J. Biol. Chem. (2004) [Pubmed]
  29. FADD/MORT1 is a common mediator of CD95 (Fas/APO-1) and tumor necrosis factor receptor-induced apoptosis. Chinnaiyan, A.M., Tepper, C.G., Seldin, M.F., O'Rourke, K., Kischkel, F.C., Hellbardt, S., Krammer, P.H., Peter, M.E., Dixit, V.M. J. Biol. Chem. (1996) [Pubmed]
  30. c-E10 is a caspase-recruiting domain-containing protein that interacts with components of death receptors signaling pathway and activates nuclear factor-kappaB. Costanzo, A., Guiet, C., Vito, P. J. Biol. Chem. (1999) [Pubmed]
  31. Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis. Harper, N., Hughes, M., MacFarlane, M., Cohen, G.M. J. Biol. Chem. (2003) [Pubmed]
  32. FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis. 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. J. Biol. Chem. (1997) [Pubmed]
  33. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Schneider, P., Thome, M., Burns, K., Bodmer, J.L., Hofmann, K., Kataoka, T., Holler, N., Tschopp, J. Immunity (1997) [Pubmed]
  34. A GTP-binding adapter protein couples TRAIL receptors to apoptosis-inducing proteins. Miyazaki, T., Reed, J.C. Nat. Immunol. (2001) [Pubmed]
  35. Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases. Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., Litwack, G., Alnemri, E.S. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  36. Interferon gamma induces upregulation and activation of caspases 1, 3, and 8 to produce apoptosis in human erythroid progenitor cells. Dai, C., Krantz, S.B. Blood (1999) [Pubmed]
  37. Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex. Rasper, D.M., Vaillancourt, J.P., Hadano, S., Houtzager, V.M., Seiden, I., Keen, S.L., Tawa, P., Xanthoudakis, S., Nasir, J., Martindale, D., Koop, B.F., Peterson, E.P., Thornberry, N.A., Huang, J., MacPherson, D.P., Black, S.C., Hornung, F., Lenardo, M.J., Hayden, M.R., Roy, S., Nicholson, D.W. Cell Death Differ. (1998) [Pubmed]
  38. NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Huang, B., Eberstadt, M., Olejniczak, E.T., Meadows, R.P., Fesik, S.W. Nature (1996) [Pubmed]
  39. Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. Aragane, Y., Kulms, D., Metze, D., Wilkes, G., Pöppelmann, B., Luger, T.A., Schwarz, T. J. Cell Biol. (1998) [Pubmed]
  40. Involvement of Fas (APO-1/CD-95) during photodynamic-therapy-mediated apoptosis in human epidermoid carcinoma A431 cells. Ahmad, N., Gupta, S., Feyes, D.K., Mukhtar, H. J. Invest. Dermatol. (2000) [Pubmed]
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