Skip to main content
Article
Licensed
Unlicensed Requires Authentication

Principles and mechanisms of CD95 activation

  • Harald Wajant is Professor at the Department of Internal Medicine II of the University Hospital Würzburg and head of the Division of Molecular Internal Medicine. He graduated in the Institute of Botany of the University of Stuttgart, Germany in 1993 and was then a postdoctoral research fellow and group leader at the Institute of Cell Biology and Immunology. Since 2003 he is Professor at the University Hospital Würzburg. His current research interests are the mechanisms of TNF receptor activation, apoptotic and non-apoptotic death receptor signaling and the development of antibodies and TNF ligand fusion proteins targeting TNF receptors.

    EMAIL logo
Published/Copyright: September 16, 2014

Abstract

CD95 (Apo1/Fas) has been originally identified as the target of cell death-inducing antibodies. The recognition of CD95 as an apoptosis-triggering receptor represents one of the early milestones in the apoptosis field. Moreover, the research on CD95-induced cell death fostered various other discoveries of broad and general relevance in cell biology, for example, the identification of caspase 8 as the initiator caspase of the extrinsic apoptosis pathway. Activation of CD95-associated intracellular signaling pathways is not a simple consequence of ligand binding but is the fine-tuned result of a complex interplay of various molecular mechanisms that eventually determine the strength and quality of the CD95 response. There is growing evidence that different forms of CD95 stimulation trigger the assembly of CD95 signaling complexes of distinct composition. Moreover, the formation of signaling competent CD95 complexes is a multistep process and the subject of regulation by various cellular cues. This review addresses the relevance of the molecular nature of the CD95-stimulating agonist for the quality of the CD95 response and discusses the importance of modification, clustering, internalization, and lipid raft and actin association of CD95 for CD95 activity.


Corresponding author: Harald Wajant, Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, D-97070 Würzburg, Germany, e-mail:

About the author

Harald Wajant

Harald Wajant is Professor at the Department of Internal Medicine II of the University Hospital Würzburg and head of the Division of Molecular Internal Medicine. He graduated in the Institute of Botany of the University of Stuttgart, Germany in 1993 and was then a postdoctoral research fellow and group leader at the Institute of Cell Biology and Immunology. Since 2003 he is Professor at the University Hospital Würzburg. His current research interests are the mechanisms of TNF receptor activation, apoptotic and non-apoptotic death receptor signaling and the development of antibodies and TNF ligand fusion proteins targeting TNF receptors.

Acknowledgments

This work was supported by Deutsche Forschungsgemeinschaft (grant Wa 1025/24-1).

References

Algeciras-Schimnich, A. and Peter, M.E. (2003). Actin dependent CD95 internalization is specific for Type I cells. FEBS Lett. 546, 185–188.Search in Google Scholar

Algeciras-Schimnich, A., Shen, L., Barnhart, B.C., Murmann, A.E., Burkhardt, J.K., and Peter, M.E. (2002). Molecular ordering of the initial signaling events of CD95. Mol. Cell. Biol. 22, 207–220.Search in Google Scholar

Aoki, K., Kurooka, M., Chen, J.J., Petryniak, J., Nabel, E.G., and Nabel, G.J. (2001). Extracellular matrix interacts with soluble CD95L: retention and enhancement of cytotoxicity. Nat. Immunol. 2, 333–337.Search in Google Scholar

Bajorath, J. (1999). Analysis of Fas-ligand interactions using a molecular model of the receptor-ligand interface. J. Comput Aided Mol. Des. 13, 409–418.Search in Google Scholar

Barnhart, B.C., Alappat, E.C., and Peter, M.E. (2003). The CD95 type I/type II model. Semin. Immunol. 15, 185–193.Search in Google Scholar

Beneteau, M., Pizon, M., Chaigne-Delalande, B., Daburon, S., Moreau, P., De Giorgi, F., Ichas, F., Rebillard, A., Dimanche-Boitrel, M.T., Taupin, J.L., et al. (2008). Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway. Mol. Cancer Res. 6, 604–613.Search in Google Scholar

Berg, D., Lehne, M., Muller, N., Siegmund, D., Munkel, S., Sebald, W., Pfizenmaier, K., and Wajant, H. (2007). Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L. Cell Death Differ. 14, 2021–2034.Search in Google Scholar

Bodmer, J.L., Schneider, P., and Tschopp, J. (2002). The molecular architecture of the TNF superfamily. Trends Biochem. Sci. 27, 19–26.Search in Google Scholar

Bremer, E., ten Cate, B., Samplonius, D.F., de Leij, L.F., and Helfrich, W. (2006). CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia. Blood 107, 2863–2870.Search in Google Scholar

Bremer, E., ten Cate, B., Samplonius, D.F., Mueller, N., Wajant, H., Stel, A.J., Chamuleau, M., van de Loosdrecht, A.A., Stieglmaier, J., Fey, G.H., et al. (2008). Superior activity of fusion protein scFvRit:sFasL over cotreatment with rituximab and Fas agonists. Cancer Res. 68, 597–604.Search in Google Scholar

Brint, E., O’Callaghan, G., and Houston, A. (2013). Life in the Fas lane: differential outcomes of Fas signaling. Cell. Mol. Life Sci. 70, 4085–4099.Search in Google Scholar

Cahuzac, N., Baum, W., Kirkin, V., Conchonaud, F., Wawrezinieck, L., Marguet, D., Janssen, O., Zornig, M., and Hueber, A.O. (2006). Fas ligand is localized to membrane rafts, where it displays increased cell death-inducing activity. Blood 107, 2384–2391.Search in Google Scholar

Celeste Morley, S., Sun, G.P., and Bierer, B.E. (2003). Inhibition of actin polymerization enhances commitment to and execution of apoptosis induced by withdrawal of trophic support. J. Cell. Biochem. 88, 1066–1076.Search in Google Scholar

Chaigne-Delalande, B., Mahfouf, W., Daburon, S., Moreau, J.F., and Legembre, P. (2009). CD95 engagement mediates actin-independent and -dependent apoptotic signals. Cell Death Differ. 16, 1654–1664.Search in Google Scholar

Chakrabandhu, K., Herincs, Z., Huault, S., Dost, B., Peng, L., Conchonaud, F., Marguet, D., He, H.T., and Hueber, A.O. (2007). Palmitoylation is required for efficient Fas cell death signaling. EMBO J. 26, 209–220.Search in Google Scholar

Chakrabandhu, K., Huault, S., Garmy, N., Fantini, J., Stebe, E., Mailfert, S., Marguet, D., and Hueber, A.O. (2008). The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand. Cell Death Differ. 15, 1824–1837.Search in Google Scholar

Chan, F.K. (2007). Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 37, 101–107.Search in Google Scholar

Cremesti, A., Paris, F., Grassme, H., Holler, N., Tschopp, J., Fuks, Z., Gulbins, E., and Kolesnick, R. (2001). Ceramide enables fas to cap and kill. J. Biol. Chem. 276, 23954–23961.Search in Google Scholar

Degli Esposti, M., Tour, J., Ouasti, S., Ivanova, S., Matarrese, P., Malorni, W., and Khosravi-Far, R. (2009). Fas death receptor enhances endocytic membrane traffic converging into the Golgi region. Mol. Biol. Cell 20, 600–615.Search in Google Scholar

Delmas, D., Rebe, C., Lacour, S., Filomenko, R., Athias, A., Gambert, P., Cherkaoui-Malki, M., Jannin, B., Dubrez-Daloz, L., Latruffe, N., et al. (2003). Resveratrol-induced apoptosis is associated with Fas redistribution in the rafts and the formation of a death-inducing signaling complex in colon cancer cells. J. Biol. Chem 278, 41482–41490.Search in Google Scholar

De Maria, R., Rippo, M.R., Schuchman, E.H., and Testi, R. (1998). Acidic sphingomyelinase (ASM) is necessary for fas-induced GD3 ganglioside accumulation and efficient apoptosis of lymphoid cells. J. Exp. Med 187, 897–902.Search in Google Scholar

DeMorrow, S., Glaser, S., Francis, H., Venter, J., Vaculin, B., Vaculin, S., and Alpini, G. (2007). Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts. J. Biol. Chem. 282, 13098–13113.Search in Google Scholar

Desbarats, J., Birge, R.B., Mimouni-Rongy, M., Weinstein, D.E., Palerme, J.S., and Newell, M.K. (2003). Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat. Cell Biol. 5, 118–125.Search in Google Scholar

Dhein, J., Daniel, P.T., Trauth, B.C., Oehm, A., Moller, P., and Krammer, P.H. (1992). Induction of apoptosis by monoclonal antibody anti-APO-1 class switch variants is dependent on cross-linking of APO-1 cell surface antigens. J. Immunol. 149, 3166–3173.Search in Google Scholar

Dickens, L.S., Boyd, R.S., Jukes-Jones, R., Hughes, M.A., Robinson, G.L., Fairall, L., Schwabe, J.W., Cain, K., and Macfarlane, M. (2012a). A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol. Cell 47, 291–305.Search in Google Scholar

Dickens, L.S., Powley, I.R., Hughes, M.A., and MacFarlane, M. (2012b). The ‘complexities’ of life and death: death receptor signalling platforms. Exp. Cell Res. 318, 1269–1277.Search in Google Scholar

Du, C., Fang, M., Li, Y., Li, L., and Wang, X. (2000). Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42.Search in Google Scholar

Edelmann, B., Bertsch, U., Tchikov, V., Winoto-Morbach, S., Perrotta, C., Jakob, M., Adam-Klages, S., Kabelitz, D., and Schütze, S. (2011). Caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes. EMBO J. 30, 379–394.Search in Google Scholar

Ehrenschwender, M., Siegmund, D., Wicovsky, A., Kracht, M., Dittrich-Breiholz, O., Spindler, V., Waschke, J., Kalthoff, H., Trauzold, A., and Wajant, H. (2010). Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation. Cell Death Differ. 17, 1435–1447.Search in Google Scholar

Elyassaki, W. and Wu, S. (2006). Lipid rafts mediate ultraviolet light-induced Fas aggregation in M624 melanoma cells. Photochem. Photobiol. 82, 787–792.Search in Google Scholar

Engels, I.H., Stepczynska, A., Stroh, C., Lauber, K., Berg, C., Schwenzer, R., Wajant, H., Janicke, R.U., Porter, A.G., Belka, C., et al. (2000). Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 19, 4563–4573.Search in Google Scholar

Eramo, A., Sargiacomo, M., Ricci-Vitiani, L., Todaro, M., Stassi, G., Messina, C.G., Parolini, I., Lotti, F., Sette, G., Peschle, C., et al. (2004). CD95 death-inducing signaling complex formation and internalization occur in lipid rafts of type I and type II cells. Eur. J. Immunol. 34, 1930–1940.Search in Google Scholar

Esposito, D., Sankar, A., Morgner, N., Robinson, C.V., Rittinger, K., and Driscoll, P.C. (2010). Solution NMR investigation of the CD95/FADD homotypic death domain complex suggests lack of engagement of the CD95 C-terminus. Structure 18, 1378–1390.Search in Google Scholar

Fanzo, J.C., Lynch, M.P., Phee, H., Hyer, M., Cremesti, A., Grassme, H., Norris, J.S., Coggeshall, K.M., Rueda, B.R., Pernis, A.B., et al. (2003). CD95 rapidly clusters in cells of diverse origins. Cancer Biol. Ther. 2, 392–395.Search in Google Scholar

Feig, C., Tchikov, V., Schutze, S., and Peter, M.E. (2007). Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling. EMBO J. 26, 221–231.Search in Google Scholar

Ferreira, K.S., Kreutz, C., Macnelly, S., Neubert, K., Haber, A., Bogyo, M., Timmer, J., and Borner, C. (2012). Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes. Apoptosis 17, 503–515.Search in Google Scholar

Fumarola, C., Zerbini, A., and Guidotti, G.G. (2001). Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis. Cell Death Differ. 8, 1004–1013.Search in Google Scholar

Gajate, C. and Mollinedo, F. (2001). The antitumor ether lipid ET-18-OCH(3) induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood 98, 3860–3863.Search in Google Scholar

Gajate, C. and Mollinedo, F. (2005). Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J. Biol. Chem. 280, 11641–11647.Search in Google Scholar

Gajate, C. and Mollinedo, F. (2007). Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood 109, 711–719.Search in Google Scholar

Gajate, C., Fonteriz, R.I., Cabaner, C., Alvarez-Noves, G., Alvarez-Rodriguez, Y., Modolell, M., and Mollinedo, F. (2000). Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis. Int J. Cancer 85, 674–682.Search in Google Scholar

Gillissen, B., Richter, A., Overkamp, T., Essmann, F., Hemmati, P.G., Preissner, R., Belka, C., and Daniel, P.T. (2013). Targeted therapy of the XIAP/proteasome pathway overcomes TRAIL-resistance in carcinoma by switching apoptosis signaling to a Bax/Bak-independent ‘type I’ mode. Cell Death Dis. 4, e643.Search in Google Scholar

Grassme, H., Cremesti, A., Kolesnick, R., and Gulbins, E. (2003). Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22, 5457–5470.Search in Google Scholar

Guicciardi, M.E. and Gores, G.J. (2009). Life and death by death receptors. FASEB J. 23, 1625–1637.Search in Google Scholar

Hebert, M., Potin, S., Sebbagh, M., Bertoglio, J., Breard, J., and Hamelin, J. (2008). Rho-ROCK-dependent ezrin-radixin-moesin phosphorylation regulates Fas-mediated apoptosis in Jurkat cells. J. Immunol. 181, 5963–5973.Search in Google Scholar

Henkler, F., Behrle, E., Dennehy, K.M., Wicovsky, A., Peters, N., Warnke, C., Pfizenmaier, K., and Wajant, H. (2005). The extracellular domains of FasL and Fas are sufficient for the formation of supramolecular FasL-Fas clusters of high stability. J. Cell Biol. 168, 1087–1098.Search in Google Scholar

Herrero, R., Kajikawa, O., Matute-Bello, G., Wang, Y., Hagimoto, N., Mongovin, S., Wong, V., Park, D.R., Brot, N., Heinecke, J.W., et al. (2011). The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region. J. Clin. Invest. 121, 1174–1190.Search in Google Scholar

Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.L., Schneider, P., Seed, B., and Tschopp, J. (2000). Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495.Search in Google Scholar

Jodo, S., Kung, J.T., Xiao, S., Chan, D.V., Kobayashi, S., Tateno, M., Lafyatis, R., and Ju, S.T. (2003). Anti-CD95-induced lethality requires radioresistant Fcγ RII+ cells. A novel mechanism for fulminant hepatic failure. J. Biol. Chem. 278, 7553–7557.Search in Google Scholar

Jost, P.J., Grabow, S., Gray, D., McKenzie, M.D., Nachbur, U., Huang, D.C., Bouillet, P., Thomas, H.E., Borner, C., Silke, J., et al. (2009). XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460, 1035–1039.Search in Google Scholar

Kamitani, T., Nguyen, H.P., and Yeh, E.T. (1997). Activation-induced aggregation and processing of the human Fas antigen. Detection with cytoplasmic domain-specific antibodies. J. Biol. Chem. 272, 22307–22314.Search in Google Scholar

Kirkin, V., Cahuzac, N., Guardiola-Serrano, F., Huault, S., Luckerath, K., Friedmann, E., Novac, N., Wels, W.S., Martoglio, B., Hueber, A.O., et al. (2007). The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. Cell Death Differ. 14, 1678–1687.Search in Google Scholar

Kirschnek, S., Paris, F., Weller, M., Grassme, H., Ferlinz, K., Riehle, A., Fuks, Z., Kolesnick, R., and Gulbins, E. (2000). CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J. Biol. Chem. 275, 27316–27323.Search in Google Scholar

Kischkel, F.C., Hellbardt, S., Behrmann, I., Germer, M., Pawlita, M., Krammer, P.H., and Peter, M.E. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 14, 5579–5588.Search in Google Scholar

Kleber, S., Sancho-Martinez, I., Wiestler, B., Beisel, A., Gieffers, C., Hill, O., Thiemann, M., Mueller, W., Sykora, J., Kuhn, A., et al. (2008). Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13, 235–248.Search in Google Scholar

Kreuz, S., Siegmund, D., Rumpf, J.J., Samel, D., Leverkus, M., Janssen, O., Hacker, G., Dittrich-Breiholz, O., Kracht, M., Scheurich, P., et al. (2004). NF-κB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J. Cell Biol. 166, 369–380.Search in Google Scholar

Kulms, D., Dussmann, H., Poppelmann, B., Stander, S., Schwarz, A., and Schwarz, T. (2002). Apoptosis induced by disruption of the actin cytoskeleton is mediated via activation of CD95 (Fas/APO-1). Cell Death Differ. 9, 598–608.Search in Google Scholar

Kuo, W.C., Yang, K.T., Hsieh, S.L., and Lai, M.Z. (2010). Ezrin is a negative regulator of death receptor-induced apoptosis. Oncogene 29, 1374–1383.Search in Google Scholar

Lacour, S., Hammann, A., Grazide, S., Lagadic-Gossmann, D., Athias, A., Sergent, O., Laurent, G., Gambert, P., Solary, E., and Dimanche-Boitrel, M.T. (2004). Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res. 64, 3593–3598.Search in Google Scholar

Lang, I., Fick, A., Schafer, V., Giner, T., Siegmund, D., and Wajant, H. (2012). Signaling active CD95 receptor molecules trigger co-translocation of inactive CD95 molecules into lipid rafts. J. Biol. Chem. 287, 24026–24042.Search in Google Scholar

Lee, K.H., Feig, C., Tchikov, V., Schickel, R., Hallas, C., Schutze, S., Peter, M.E., and Chan, A.C. (2006). The role of receptor internalization in CD95 signaling. EMBO J. 25, 1009–1023.Search in Google Scholar

Legembre, P., Beneteau, M., Daburon, S., Moreau, J.F., and Taupin, J.L. (2003). Cutting edge: SDS-stable Fas microaggregates: an early event of Fas activation occurring with agonistic anti-Fas antibody but not with Fas ligand. J. Immunol. 171, 5659–5662.Search in Google Scholar

Legembre, P., Daburon, S., Moreau, P., Moreau, J.F., and Taupin, J.L. (2006). Modulation of Fas-mediated apoptosis by lipid rafts in T lymphocytes. J. Immunol. 176, 716–720.Search in Google Scholar

Leon-Bollotte, L., Subramaniam, S., Cauvard, O., Plenchette-Colas, S., Paul, C., Godard, C., Martinez-Ruiz, A., Legembre, P., Jeannin, J.F., and Bettaieb, A. (2011). S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology 140, 2009–2018, 2018, e2001–2004.Search in Google Scholar

Lingwood, D. and Simons, K. (2010). Lipid rafts as a membrane-organizing principle. Science 327, 46–50.Search in Google Scholar

Lozupone, F., Lugini, L., Matarrese, P., Luciani, F., Federici, C., Iessi, E., Margutti, P., Stassi, G., Malorni, W., and Fais, S. (2004). Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J. Biol. Chem. 279, 9199–9207.Search in Google Scholar

Luciani, F., Matarrese, P., Giammarioli, A.M., Lugini, L., Lozupone, F., Federici, C., Iessi, E., Malorni, W., and Fais, S. (2004). CD95/phosphorylated ezrin association underlies HIV-1GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+ T lymphocytes. Cell Death Differ. 11, 574–582.Search in Google Scholar

Malleter, M., Tauzin, S., Bessede, A., Castellano, R., Goubard, A., Godey, F., Leveque, J., Jezequel, P., Campion, L., Campone, M., et al. (2013). CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer. Cancer Res. 73, 6711–6721.Search in Google Scholar

Matarrese, P., Manganelli, V., Garofalo, T., Tinari, A., Gambardella, L., Ndebele, K., Khosravi-Far, R., Sorice, M., Esposti, M.D., and Malorni, W. (2008). Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells. Biochem. J. 413, 467–478.Search in Google Scholar

Matsuno, H., Yudoh, K., Watanabe, Y., Nakazawa, F., Aono, H., and Kimura, T. (2001). Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand. J. Rheumatol. 28, 22–28.Search in Google Scholar

Meng, Y., Kang, S., and Fishman, D.A. (2005). Lysophosphatidic acid inhibits anti-Fas-mediated apoptosis enhanced by actin depolymerization in epithelial ovarian cancer. FEBS Lett. 579, 1311–1319.Search in Google Scholar

Micheau, O., Solary, E., Hammann, A., and Dimanche-Boitrel, M.T. (1999). Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J. Biol. Chem. 274, 7987–7992.Search in Google Scholar

Mitsiades, N., Yu, W.H., Poulaki, V., Tsokos, M., and Stamenkovic, I. (2001). Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res. 61, 577–581.Search in Google Scholar

Miyaji, M., Jin, Z.X., Yamaoka, S., Amakawa, R., Fukuhara, S., Sato, S.B., Kobayashi, T., Domae, N., Mimori, T., Bloom, E.T., et al. (2005). Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis. J. Exp. Med. 202, 249–259.Search in Google Scholar

Moretti, S., Procopio, A., Lazzarini, R., Rippo, M.R., Testa, R., Marra, M., Tamagnone, L., and Catalano, A. (2008). Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts. Blood 111, 2290–2299.Search in Google Scholar

Muppidi, J.R. and Siegel, R.M. (2004). Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nat. Immunol. 5, 182–189.Search in Google Scholar

Nachbur, U., Kassahn, D., Yousefi, S., Legler, D.F., and Brunner, T. (2006). Posttranscriptional regulation of Fas (CD95) ligand killing activity by lipid rafts. Blood 107, 2790–2796.Search in Google Scholar

Ndozangue-Touriguine, O., Sebbagh, M., Merino, D., Micheau, O., Bertoglio, J., and Breard, J. (2008). A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma. Oncogene 27, 6012–6022.Search in Google Scholar

Papoff, G., Hausler, P., Eramo, A., Pagano, M.G., Di Leve, G., Signore, A., and Ruberti, G. (1999). Identification and characterization of a ligand-independent oligomerization domain in the extracellular region of the CD95 death receptor. J. Biol. Chem. 274, 38241–38250.Search in Google Scholar

Paris, F., Grassme, H., Cremesti, A., Zager, J., Fong, Y., Haimovitz-Friedman, A., Fuks, Z., Gulbins, E., and Kolesnick, R. (2001). Natural ceramide reverses Fas resistance of acid sphingomyelinase-/- hepatocytes. J. Biol. Chem. 276, 8297–8305.Search in Google Scholar

Park, M.A., Zhang, G., Martin, A.P., Hamed, H., Mitchell, C., Hylemon, P.B., Graf, M., Rahmani, M., Ryan, K., Liu, X., et al. (2008). Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation. Cancer Biol. Ther. 7, 1648–1662.Search in Google Scholar

Park, M.A., Mitchell, C., Zhang, G., Yacoub, A., Allegood, J., Haussinger, D., Reinehr, R., Larner, A., Spiegel, S., Fisher, P.B., et al. (2010). Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca2+-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. Cancer Res. 70, 6313–6324.Search in Google Scholar

Parlato, S., Giammarioli, A.M., Logozzi, M., Lozupone, F., Matarrese, P., Luciani, F., Falchi, M., Malorni, W., and Fais, S. (2000). CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway. EMBO J. 19, 5123–5134.Search in Google Scholar

Petrovas, C., Mueller, Y.M., Yang, G., Altork, S.R., Jacobson, J.M., Pitsakis, P.G., Mounzer, K.C., Altman, J.D., and Katsikis, P.D. (2007). Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells. Apoptosis 12, 2175–2186.Search in Google Scholar

Pizon, M., Rampanarivo, H., Tauzin, S., Chaigne-Delalande, B., Daburon, S., Castroviejo, M., Moreau, P., Moreau, J.F., and Legembre, P. (2011). Actin-independent exclusion of CD95 by PI3K/AKT signalling: implications for apoptosis. Eur. J. Immunol. 41, 2368–2378.Search in Google Scholar

Rossin, A., Kral, R., Lounnas, N., Chakrabandhu, K., Mailfert, S., Marguet, D., and Hueber, A.O. (2010). Identification of a lysine-rich region of Fas as a raft nanodomain targeting signal necessary for Fas-mediated cell death. Exp. Cell Res. 316, 1513–1522.Search in Google Scholar

Ruan, W., Lee, C.T., and Desbarats, J. (2008). A novel juxtamembrane domain in tumor necrosis factor receptor superfamily molecules activates Rac1 and controls neurite growth. Mol. Biol. Cell 19, 3192–3202.Search in Google Scholar

Samel, D., Muller, D., Gerspach, J., Assohou-Luty, C., Sass, G., Tiegs, G., Pfizenmaier, K., and Wajant, H. (2003). Generation of a FasL-based proapoptotic fusion protein devoid of systemic toxicity due to cell-surface antigen-restricted activation. J. Biol. Chem. 278, 32077–32082.Search in Google Scholar

Scaffidi, C., Fulda, S., Srinivasan, A., Friesen, C., Li, F., Tomaselli, K.J., Debatin, K.M., Krammer, P.H., and Peter, M.E. (1998). Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675–1687.Search in Google Scholar

Schleich, K., Warnken, U., Fricker, N., Oztürk, S., Richter, P., Kammerer, K., Schnölzer, M., Krammer, P.H., and Lavrik, I.N. (2012). Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol. Cell 47, 306–319.Search in Google Scholar

Schneider, P., Bodmer, J.L., Holler, N., Mattmann, C., Scuderi, P., Terskikh, A., Peitsch, M.C., and Tschopp, J. (1997). Characterization of Fas (Apo-1, CD95)-Fas ligand interaction. J. Biol. Chem. 272, 18827–18833.Search in Google Scholar

Schneider, P., Holler, N., Bodmer, J.L., Hahne, M., Frei, K., Fontana, A., and Tschopp, J. (1998). Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity. J. Exp. Med. 187, 1205–1213.Search in Google Scholar

Schulte, M., Reiss, K., Lettau, M., Maretzky, T., Ludwig, A., Hartmann, D., de Strooper, B., Janssen, O., and Saftig, P. (2007). ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death. Cell Death Differ. 14, 1040–1049.Search in Google Scholar

Sessler, T., Healy, S., Samali, A., and Szegezdi, E. (2013). Structural determinants of DISC function: new insights into death receptor-mediated apoptosis signalling. Pharmacol Ther. 140, 186–199.Search in Google Scholar

Siegel, R.M., Martin, D.A., Zheng, L., Ng, S.Y., Bertin, J., Cohen, J., and Lenardo, M.J. (1998). Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J. Cell Biol. 141, 1243–1253.Search in Google Scholar

Siegel, R.M., Frederiksen, J.K., Zacharias, D.A., Chan, F.K., Johnson, M., Lynch, D., Tsien, R.Y., and Lenardo, M.J. (2000). Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288, 2354–2357.Search in Google Scholar

Siegel, R.M., Muppidi, J.R., Sarker, M., Lobito, A., Jen, M., Martin, D., Straus, S.E., and Lenardo, M.J. (2004). SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. J. Cell Biol. 167, 735–744.Search in Google Scholar

Siegmund, D., Wicovsky, A., Schmitz, I., Schulze-Osthoff, K., Kreuz, S., Leverkus, M., Dittrich-Breiholz, O., Kracht, M., and Wajant, H. (2005). Death receptor-induced signaling pathways are differentially regulated by gamma interferon upstream of caspase 8 processing. Mol. Cell. Biol. 25, 6363–6379.Search in Google Scholar

Siegmund, D., Klose, S., Zhou, D., Baumann, B., Roder, C., Kalthoff, H., Wajant, H., and Trauzold, A. (2007). Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells. Cell. Signal. 19, 1172–1184.Search in Google Scholar

Soderstrom, T.S., Nyberg, S.D., and Eriksson, J.E. (2005). CD95 capping is ROCK-dependent and dispensable for apoptosis. J. Cell Sci. 118, 2211–2223.Search in Google Scholar

Starling, G.C., Bajorath, J., Emswiler, J., Ledbetter, J.A., Aruffo, A., and Kiener, P.A. (1997). Identification of amino acid residues important for ligand binding to Fas. J. Exp. Med. 185, 1487–1492.Search in Google Scholar

Stegh, A.H., Barnhart, B.C., Volkland, J., Algeciras-Schimnich, A., Ke, N., Reed, J.C., and Peter, M.E. (2002). Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein. J. Biol. Chem. 277, 4351–4360.Search in Google Scholar

Stoicov, C., Cai, X., Li, H., Klucevsek, K., Carlson, J., Saffari, R., and Houghton, J. (2005). Major histocompatibility complex class II inhibits fas antigen-mediated gastric mucosal cell apoptosis through actin-dependent inhibition of receptor aggregation. Infect. Immun. 73, 6311–6321.Search in Google Scholar

Stroh, C. and Schulze-Osthoff, K. (1998). Death by a thousand cuts: an ever increasing list of caspase substrates. Cell Death Differ. 5, 997–1000.Search in Google Scholar

Subauste, M.C., Von Herrath, M., Benard, V., Chamberlain, C.E., Chuang, T.H., Chu, K., Bokoch, G.M., and Hahn, K.M. (2000). Rho family proteins modulate rapid apoptosis induced by cytotoxic T lymphocytes and Fas. J. Biol. Chem. 275, 9725–9733.Search in Google Scholar

Suda, T., Tanaka, M., Miwa, K., and Nagata, S. (1996). Apoptosis of mouse naive T cells induced by recombinant soluble Fas ligand and activation-induced resistance to Fas ligand. J. Immunol. 157, 3918–3924.Search in Google Scholar

Suda, T., Hashimoto, H., Tanaka, M., Ochi, T., and Nagata, S. (1997). Membrane Fas ligand kills human peripheral blood T lymphocytes, and soluble Fas ligand blocks the killing. J. Exp. Med. 186, 2045–2050.Search in Google Scholar

Tanaka, M., Suda, T., Takahashi, T., and Nagata, S. (1995). Expression of the functional soluble form of human fas ligand in activated lymphocytes. EMBO J. 14, 1129–1135.Search in Google Scholar

Tanaka, M., Itai, T., Adachi, M., and Nagata, S. (1998). Downregulation of Fas ligand by shedding. Nat. Med. 4, 31–36.Search in Google Scholar

Tauzin, S., Chaigne-Delalande, B., Selva, E., Khadra, N., Daburon, S., Contin-Bordes, C., Blanco, P., Le Seyec, J., Ducret, T., Counillon, L., et al. (2011). The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway. PLoS Biol. 9, e1001090.Search in Google Scholar

Tauzin, S., Debure, L., Moreau, J.F., and Legembre, P. (2012). CD95-mediated cell signaling in cancer: mutations and post-translational modulations. Cell. Mol. Life Sci. 69, 1261–1277.Search in Google Scholar

Thurau, M., Everett, H., Tapernoux, M., Tschopp, J., and Thome, M. (2006). The TRAF3-binding site of human molluscipox virus FLIP molecule MC159 is critical for its capacity to inhibit Fas-induced apoptosis. Cell Death Differ. 13, 1577–1585.Search in Google Scholar

Tinsley, K.W., Herzog, D., and Leitenberg, D. (2011). CD4 co-receptor dependent signaling promotes competency for re-stimulation induced cell death of effector T cells. Cell. Immunol. 266, 200–207.Search in Google Scholar

Vargo-Gogola, T., Crawford, H.C., Fingleton, B., and Matrisian, L.M. (2002). Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch. Biochem. Biophys. 408, 155–161.Search in Google Scholar

Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., and Vaux, D.L. (2000). Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 43–53.Search in Google Scholar

Vogler, M., Walczak, H., Stadel, D., Haas, T.L., Genze, F., Jovanovic, M., Gschwend, J.E., Simmet, T., Debatin, K.M., and Fulda, S. (2008). Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. Cancer Res. 68, 7956–7965.Search in Google Scholar

Walker, T., Mitchell, C., Park, M.A., Yacoub, A., Rahmani, M., Haussinger, D., Reinehr, R., Voelkel-Johnson, C., Fisher, P.B., Grant, S., et al. (2010). 17-Allylamino-17-demethoxygeldanamycin and MEK1/2 inhibitors kill GI tumor cells via Ca2+-dependent suppression of GRP78/BiP and induction of ceramide and reactive oxygen species. Mol. Cancer Ther. 9, 1378–1395.Search in Google Scholar

Wang, L., Yang, J.K., Kabaleeswaran, V., Rice, A.J., Cruz, A.C., Park, A.Y., Yin, Q., Damko, E., Jang, S.B., Raunser, S., et al. (2010). The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat. Struct Mol. Biol. 17, 1324–1329.Search in Google Scholar

Wilson, T.R., McEwan, M., McLaughlin, K., Le Clorennec, C., Allen, W.L., Fennell, D.A., Johnston, P.G., and Longley, D.B. (2009). Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells. Oncogene 28, 63–72.Search in Google Scholar

Xu, Y., Szalai, A.J., Zhou, T., Zinn, K.R., Chaudhuri, T.R., Li, X., Koopman, W.J., and Kimberly, R.P. (2003). Fc gamma Rs modulate cytotoxicity of anti-Fas antibodies: implications for agonistic antibody-based therapeutics. J. Immunol. 171, 562–568.Search in Google Scholar

Xu, Z.X., Ding, T., Haridas, V., Connolly, F., and Gutterman, J.U. (2009). Avicin D, a plant triterpenoid, induces cell apoptosis by recruitment of Fas and downstream signaling molecules into lipid rafts. PLoS One 4, e8532.Search in Google Scholar

Zhang, G., Park, M.A., Mitchell, C., Hamed, H., Rahmani, M., Martin, A.P., Curiel, D.T., Yacoub, A., Graf, M., Lee, R., et al. (2008). Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. Clin. Cancer Res. 14, 5385–5399.Search in Google Scholar

Zhuang, S. and Kochevar, I.E. (2003). Ultraviolet A radiation induces rapid apoptosis of human leukemia cells by Fas ligand-independent activation of the Fas death pathways. Photochem. Photobiol. 78, 61–67.Search in Google Scholar

Received: 2014-6-13
Accepted: 2014-8-6
Published Online: 2014-9-16
Published in Print: 2014-12-1

©2014 by De Gruyter

Downloaded on 7.5.2026 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2014-0212/html?lang=en
Scroll to top button