Skip to main content

Advertisement

SpringerLink
Log in

CD95-mediated cell signaling in cancer: mutations and post-translational modulations

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Apoptosis has emerged as a fundamental process important in tissue homeostasis, immune response, and during development. CD95 (also known as Fas), a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been initially cloned as a death receptor. Its cognate ligand, CD95L, is mainly found at the plasma membrane of activated T-lymphocytes and natural killer cells where it contributes to the elimination of transformed and infected cells. According to its implication in the immune homeostasis and immune surveillance, and since several malignant cells of various histological origins exhibit loss-of-function mutations, which cause resistance towards the CD95-mediated apoptotic signal, CD95 has been classified as a tumor suppressor gene. Nevertheless, this assumption has been recently challenged, as in certain pathophysiological contexts, CD95 engagement transmits non-apoptotic signals that promote inflammation, carcinogenesis or liver/peripheral nerve regeneration. The focus of this review is to discuss these apparent contradictions of the known function(s) of CD95.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ASM:

Acid sphingomyelinase

ADAM:

A disintegrin and metalloproteinase domain

ALPS:

Autoimmune lymphoproliferative syndrome

DD:

Death domain

FADD:

Fas-associating protein with a death domain

GC:

Germinal center

LOH:

Loss of heterozygosity

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloproteinase

NF-κB:

Nuclear factor Kappa B

TNF:

Tumor necrosis factor

References

  1. Behrmann I, Walczak H, Krammer PH (1994) Structure of the human APO-1 gene. Eur J Immunol 24:3057–3062

    Article  PubMed  CAS  Google Scholar 

  2. Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243

    Article  PubMed  CAS  Google Scholar 

  3. Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, Debatin KM, Krammer PH (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245:301–305

    Article  PubMed  CAS  Google Scholar 

  4. Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S (1994) Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969–976

    Article  PubMed  CAS  Google Scholar 

  5. Montel AH, Bochan MR, Hobbs JA, Lynch DH, Brahmi Z (1995) Fas involvement in cytotoxicity mediated by human NK cells. Cell Immunol 166:236–246

    Article  PubMed  CAS  Google Scholar 

  6. Saas P, Walker PR, Hahne M, Quiquerez AL, Schnuriger V, Perrin G, French L, Van Meir EG, de Tribolet N, Tschopp J, Dietrich PY (1997) Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain? J Clin Invest 99:1173–1178

    Article  PubMed  CAS  Google Scholar 

  7. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA (1995) Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270:1189–1192

    Article  PubMed  CAS  Google Scholar 

  8. Stuart PM, Griffith TS, Usui N, Pepose J, Yu X, Ferguson TA (1997) CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J Clin Invest 99:396–402

    Article  PubMed  CAS  Google Scholar 

  9. Bellgrau D, Gold D, Selawry H, Moore J, Franzusoff A, Duke RC (1995) A role for CD95 ligand in preventing graft rejection. Nature 377:630–632

    Article  PubMed  CAS  Google Scholar 

  10. Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J, Tschopp J, Tschopp J (1996) Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366

    Article  PubMed  CAS  Google Scholar 

  11. O’Connell J, O’Sullivan GC, Collins JK, Shanahan F (1996) The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 184:1075–1082

    Article  PubMed  Google Scholar 

  12. Allison J, Georgiou HM, Strasser A, Vaux DL (1997) Transgenic expression of CD95 ligand on islet beta cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc Natl Acad Sci USA 94:3943–3947

    Article  PubMed  CAS  Google Scholar 

  13. Kang SM, Schneider DB, Lin Z, Hanahan D, Dichek DA, Stock PG, Baekkeskov S (1997) Fas ligand expression in islets of Langerhans does not confer immune privilege and instead targets them for rapid destruction. Nat Med 3:738–743

    Article  PubMed  CAS  Google Scholar 

  14. Chen JJ, Sun Y, Nabel GJ (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282:1714–1717

    Article  PubMed  CAS  Google Scholar 

  15. Letellier E, Kumar S, Sancho-Martinez I, Krauth S, Funke-Kaiser A, Laudenklos S, Konecki K, Klussmann S, Corsini NS, Kleber S, Drost N, Neumann A, Levi-Strauss M, Brors B, Gretz N, Edler L, Fischer C, Hill O, Thiemann M, Biglari B, Karray S, Martin-Villalba A (2010) CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site. Immunity 32:240–252

    Article  PubMed  CAS  Google Scholar 

  16. O’Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang JG, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A (2009) Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461:659–663

    Article  CAS  Google Scholar 

  17. Tauzin S, Chaigne-Delalande B, Selva E, Khadra N, Daburon S, Contin-Bordes C, Blanco P, Le Seyec J, Ducret T, Counillon L, Moreau JF, Hofman P, Vacher P, Legembre P (2011) The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway. PLoS Biol 9:e1001090

    Article  PubMed  CAS  Google Scholar 

  18. Bivona TG, Hieronymus H, Parker J, Chang K, Taron M, Rosell R, Moonsamy P, Dahlman K, Miller VA, Costa C, Hannon G, Sawyers CL (2011) FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471:523–526

    Article  PubMed  CAS  Google Scholar 

  19. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME (2010) CD95 promotes tumour growth. Nature 465:492–496

    Article  PubMed  CAS  Google Scholar 

  20. Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O, Thiemann M, Mueller W, Sykora J, Kuhn A, Schreglmann N, Letellier E, Zuliani C, Klussmann S, Teodorczyk M, Grone HJ, Ganten TM, Sultmann H, Tuttenberg J, von Deimling A, Regnier-Vigouroux A, Herold-Mende C, Martin-Villalba A (2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13:235–248

    Article  PubMed  CAS  Google Scholar 

  21. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ (2000) A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 288:2351–2354

    Article  PubMed  CAS  Google Scholar 

  22. Papoff G, Hausler P, Eramo A, Pagano MG, Di Leve G, Signore A, 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

    Article  PubMed  CAS  Google Scholar 

  23. Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, Tsien RY, Lenardo MJ (2000) Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288:2354–2357

    Article  PubMed  CAS  Google Scholar 

  24. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW (1996) NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature 384:638–641

    Article  PubMed  CAS  Google Scholar 

  25. Scott FL, Stec B, Pop C, Dobaczewska MK, Lee JJ, Monosov E, Robinson H, Salvesen GS, Schwarzenbacher R, Riedl SJ (2009) The Fas-FADD death domain complex structure unravels signalling by receptor clustering. Nature 457:1019–1022

    Article  PubMed  CAS  Google Scholar 

  26. Esposito D, Sankar A, Morgner N, Robinson CV, Rittinger K, Driscoll PC (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

    Article  PubMed  CAS  Google Scholar 

  27. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H (2010) The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations. Nat Struct Mol Biol 17:1324–1329

    Article  PubMed  CAS  Google Scholar 

  28. Muppidi JR, Lobito AA, Ramaswamy M, Yang JK, Wang L, Wu H, Siegel RM (2006) Homotypic FADD interactions through a conserved RXDLL motif are required for death receptor-induced apoptosis. Cell Death Differ 13:1641–1650

    Article  PubMed  CAS  Google Scholar 

  29. Kischkel FC, Hellbardt S, Behrmann I, Germer M, Pawlita M, Krammer PH, Peter ME (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588

    PubMed  CAS  Google Scholar 

  30. Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195

    Article  PubMed  CAS  Google Scholar 

  31. Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J (1997) Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386:517–521

    Article  PubMed  CAS  Google Scholar 

  32. Condorelli G, Vigliotta G, Cafieri A, Trencia A, Andalo P, Oriente F, Miele C, Caruso M, Formisano P, Beguinot F (1999) PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 18:4409–4415

    Article  PubMed  CAS  Google Scholar 

  33. Drappa J, Vaishnaw AK, Sullivan KE, Chu JL, Elkon KB (1996) Fas gene mutations in the Canale–Smith syndrome an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med 335:1643–1649

    Article  PubMed  CAS  Google Scholar 

  34. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935–946

    Article  PubMed  CAS  Google Scholar 

  35. Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349

    Article  PubMed  CAS  Google Scholar 

  36. Canale VC, Smith CH (1967) Chronic lymphadenopathy simulating malignant lymphoma. J Pediatr 70:891–899

    Article  PubMed  CAS  Google Scholar 

  37. Rieux-Laucat F, Blachere S, Danielan S, De Villartay JP, Oleastro M, Solary E, Bader-Meunier B, Arkwright P, Pondare C, Bernaudin F, Chapel H, Nielsen S, Berrah M, Fischer A, Le Deist F (1999) Lymphoproliferative syndrome with autoimmunity: a possible genetic basis for dominant expression of the clinical manifestations. Blood 94:2575–2582

    PubMed  CAS  Google Scholar 

  38. Straus SE, Jaffe ES, Puck JM, Dale JK, Elkon KB, Rosen-Wolff A, Peters AM, Sneller MC, Hallahan CW, Wang J, Fischer RE, Jackson CM, Lin AY, Baumler C, Siegert E, Marx A, Vaishnaw AK, Grodzicky T, Fleisher TA, Lenardo MJ (2001) The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98:194–200

    Article  PubMed  CAS  Google Scholar 

  39. Hennino A, Berard M, Krammer PH, Defrance T (2001) FLICE-inhibitory protein is a key regulator of germinal center B cell apoptosis. J Exp Med 193:447–458

    Article  PubMed  CAS  Google Scholar 

  40. Montesinos-Rongen M, Van Roost D, Schaller C, Wiestler OD, Deckert M (2004) Primary diffuse large B-cell lymphomas of the central nervous system are targeted by aberrant somatic hypermutation. Blood 103:1869–1875

    Article  PubMed  CAS  Google Scholar 

  41. Muschen M, Rajewsky K, Kronke M, Kuppers R (2002) The origin of CD95-gene mutations in B-cell lymphoma. Trends Immunol 23:75–80

    Article  PubMed  CAS  Google Scholar 

  42. Peter ME, Legembre P, Barnhart BC (2005) Does CD95 have tumor promoting activities? Biochim Biophys Acta 1755:25–36

    PubMed  CAS  Google Scholar 

  43. Legembre P, Barnhart BC, Peter ME (2004) The relevance of NF-kappaB for CD95 signaling in tumor cells. Cell Cycle 3:1235–1239

    Article  PubMed  CAS  Google Scholar 

  44. Legembre P, Barnhart BC, Zheng L, Vijayan S, Straus SE, Puck J, Dale JK, Lenardo M, Peter ME (2004) Induction of apoptosis and activation of NF-kappaB by CD95 require different signalling thresholds. EMBO Rep 5:1084–1089

    Article  PubMed  CAS  Google Scholar 

  45. Barnhart BC, Legembre P, Pietras E, Bubici C, Franzoso G, Peter ME (2004) CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J 23:3175–3185

    Article  PubMed  CAS  Google Scholar 

  46. Jackson CE, Fischer RE, Hsu AP, Anderson SM, Choi Y, Wang J, Dale JK, Fleisher TA, Middelton LA, Sneller MC, Lenardo MJ, Straus SE, Puck JM (1999) Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. Am J Hum Genet 64:1002–1014

    Article  PubMed  CAS  Google Scholar 

  47. Muppidi JR, Siegel RM (2004) Ligand-independent redistribution of Fas (CD95) into lipid rafts mediates clonotypic T cell death. Nat Immunol 5:182–189

    Article  PubMed  CAS  Google Scholar 

  48. Stel AJ, Ten Cate B, Jacobs S, Kok JW, Spierings DC, Dondorff M, Helfrich W, Kluin-Nelemans HC, de Leij LF, Withoff S, Kroesen BJ (2007) Fas receptor clustering and involvement of the death receptor pathway in rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to fas-induced apoptosis. J Immunol 178:2287–2295

    PubMed  CAS  Google Scholar 

  49. Delmas D, Rebe C, Lacour S, Filomenko R, Athias A, Gambert P, Cherkaoui-Malki M, Jannin B, Dubrez-Daloz L, Latruffe N, Solary E (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

    Article  PubMed  CAS  Google Scholar 

  50. Delmas D, Rebe C, Micheau O, Athias A, Gambert P, Grazide S, Laurent G, Latruffe N, Solary E (2004) Redistribution of CD95, DR4 and DR5 in rafts accounts for the synergistic toxicity of resveratrol and death receptor ligands in colon carcinoma cells. Oncogene 23:8979–8986

    Article  PubMed  CAS  Google Scholar 

  51. Beneteau M, Pizon M, Chaigne-Delalande B, Daburon S, Moreau P, De Giorgi F, Ichas F, Rebillard A, Dimanche-Boitrel MT, Taupin JL, Moreau JF, Legembre P (2008) Localization of Fas/CD95 into the lipid rafts on down-modulation of the phosphatidylinositol 3-kinase signaling pathway. Mol Cancer Res MCR 6:604–613

    Article  CAS  Google Scholar 

  52. Gajate C, Del Canto-Janez E, Acuna AU, Amat-Guerri F, Geijo E, Santos-Beneit AM, Veldman RJ, Mollinedo F (2004) Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis. J Exp Med 200:353–365

    Article  PubMed  CAS  Google Scholar 

  53. Gajate C, 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

    Article  PubMed  CAS  Google Scholar 

  54. Gajate C, 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  57. Segui B, Legembre P (2010) Redistribution of CD95 into the lipid rafts to treat cancer cells? Recent Pat Anticancer Drug Discov 5:22–28

    Article  PubMed  CAS  Google Scholar 

  58. Anathy V, Aesif SW, Guala AS, Havermans M, Reynaert NL, Ho YS, Budd RC, Janssen-Heininger YM (2009) Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas. J Cell Biol 184:241–252

    Article  PubMed  CAS  Google Scholar 

  59. Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J, Trauth BC et al (1992) Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen. J Biol Chem 267:10709–10715

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  61. Leon-Bollotte L, Subramaniam S, Cauvard O, Plenchette-Colas S, Paul C, Godard C, Martinez-Ruiz A, Legembre P, Jeannin JF, 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

    Article  PubMed  CAS  Google Scholar 

  62. Chakrabandhu K, Herincs Z, Huault S, Dost B, Peng L, Conchonaud F, Marguet D, He HT, Hueber AO (2007) Palmitoylation is required for efficient Fas cell death signaling. EMBO J 26:209–220

    Article  PubMed  CAS  Google Scholar 

  63. Feig C, Tchikov V, Schutze S, Peter ME (2007) Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling. EMBO J 26:221–231

    Article  PubMed  CAS  Google Scholar 

  64. Lee KH, Feig C, Tchikov V, Schickel R, Hallas C, Schutze S, Peter ME, Chan AC (2006) The role of receptor internalization in CD95 signaling. EMBO J 25:1009–1023

    Article  PubMed  CAS  Google Scholar 

  65. Buell JF, Gross TG, Woodle ES (2005) Malignancy after transplantation. Transplantation 80:S254–S264

    Article  PubMed  Google Scholar 

  66. Bui JD, Schreiber RD (2007) Cancer immunosurveillance, immunoediting and inflammation: independent or interdependent processes? Curr Opin Immunol 19:203–208

    Article  PubMed  CAS  Google Scholar 

  67. Beneteau M, Daburon S, Moreau JF, Taupin JL, Legembre P (2007) Dominant-negative Fas mutation is reversed by down-expression of c-FLIP. Cancer Res 67:108–115

    Article  PubMed  CAS  Google Scholar 

  68. Algeciras-Schimnich A, Pietras EM, Barnhart BC, Legembre P, Vijayan S, Holbeck SL, Peter ME (2003) Two CD95 tumor classes with different sensitivities to antitumor drugs. Proc Natl Acad Sci USA 100:11445–11450

    Article  PubMed  CAS  Google Scholar 

  69. Corsini NS, Sancho-Martinez I, Laudenklos S, Glagow D, Kumar S, Letellier E, Koch P, Teodorczyk M, Kleber S, Klussmann S, Wiestler B, Brustle O, Mueller W, Gieffers C, Hill O, Thiemann M, Seedorf M, Gretz N, Sprengel R, Celikel T, Martin-Villalba A (2009) The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. Cell Stem Cell 5:178–190

    Article  PubMed  CAS  Google Scholar 

  70. Bellone G, Smirne C, Carbone A, Mareschi K, Dughera L, Farina EC, Alabiso O, Valente G, Emanuelli G, Rodeck U (2000) Production and pro-apoptotic activity of soluble CD95 ligand in pancreatic carcinoma. Clin Cancer Res 6:2448–2455

    PubMed  CAS  Google Scholar 

  71. Tanaka M, Suda T, Haze K, Nakamura N, Sato K, Kimura F, Motoyoshi K, Mizuki M, Tagawa S, Ohga S, Hatake K, Drummond AH, Nagata S (1996) Fas ligand in human serum. Nat Med 2:317–322

    Article  PubMed  CAS  Google Scholar 

  72. Hashimoto H, Tanaka M, Suda T, Tomita T, Hayashida K, Takeuchi E, Kaneko M, Takano H, Nagata S, Ochi T (1998) Soluble Fas ligand in the joints of patients with rheumatoid arthritis and osteoarthritis. Arthritis Rheum 41:657–662

    Article  PubMed  CAS  Google Scholar 

  73. Das H, Imoto S, Murayama T, Kajimoto K, Sugimoto T, Isobe T, Nakagawa T, Nishimura R, Koizumi T (1999) Levels of soluble FasL and FasL gene expression during the development of graft-versus-host disease in DLT-treated patients. Br J Haematol 104:795–800

    Article  PubMed  CAS  Google Scholar 

  74. Kanda Y, Tanaka Y, Shirakawa K, Yatomi T, Nakamura N, Kami M, Saito T, Izutsu K, Asai T, Yuji K, Ogawa S, Honda H, Mitani K, Chiba S, Yazaki Y, Hirai H (1998) Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease. Bone Marrow Transplant 22:751–754

    Article  PubMed  CAS  Google Scholar 

  75. Tomokuni A, Otsuki T, Isozaki Y, Kita S, Ueki H, Kusaka M, Kishimoto T, Ueki A (1999) Serum levels of soluble Fas ligand in patients with silicosis. Clin Exp Immunol 118:441–444

    Article  PubMed  CAS  Google Scholar 

  76. Strauss G, Lindquist JA, Arhel N, Felder E, Karl S, Haas TL, Fulda S, Walczak H, Kirchhoff F, Debatin KM (2009) CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling. J Exp Med 206:1379–1393

    Article  PubMed  CAS  Google Scholar 

  77. Le’Negrate G, Selva E, Auberger P, Rossi B, Hofman P (2000) Sustained polymorphonuclear leukocyte transmigration induces apoptosis in T84 intestinal epithelial cells. J Cell Biol 150:1479–1488

    Article  PubMed  Google Scholar 

  78. Matsuno H, Yudoh K, Watanabe Y, Nakazawa F, Aono H, 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

    PubMed  CAS  Google Scholar 

  79. Vargo-Gogola T, Crawford HC, Fingleton B, Matrisian LM (2002) Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys 408:155–161

    Article  PubMed  CAS  Google Scholar 

  80. Kiaei M, Kipiani K, Calingasan NY, Wille E, Chen J, Heissig B, Rafii S, Lorenzl S, Beal MF (2007) Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 205:74–81

    Article  PubMed  CAS  Google Scholar 

  81. Kirkin V, Cahuzac N, Guardiola-Serrano F, Huault S, Luckerath K, Friedmann E, Novac N, Wels WS, Martoglio B, Hueber AO, Zornig M (2007) The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. Cell Death Differ 14:1678–1687

    Article  PubMed  CAS  Google Scholar 

  82. Schulte M, Reiss K, Lettau M, Maretzky T, Ludwig A, Hartmann D, de Strooper B, Janssen O, 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

    PubMed  CAS  Google Scholar 

  83. Holler N, Tardivel A, Kovacsovics-Bankowski M, Hertig S, Gaide O, Martinon F, Tinel A, Deperthes D, Calderara S, Schulthess T, Engel J, Schneider P, Tschopp J (2003) Two adjacent trimeric Fas ligands are required for Fas signaling and formation of a death-inducing signaling complex. Mol Cell Biol 23:1428–1440

    Article  PubMed  CAS  Google Scholar 

  84. Schneider P, Holler N, Bodmer JL, Hahne M, Frei K, Fontana A, 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

    Article  PubMed  CAS  Google Scholar 

  85. Suda T, Hashimoto H, Tanaka M, Ochi T, 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

    Article  PubMed  CAS  Google Scholar 

  86. Herrero R, Kajikawa O, Matute-Bello G, Wang Y, Hagimoto N, Mongovin S, Wong V, Park DR, Brot N, Heinecke JW, Rosen H, Goodman RB, Fu X, Martin TR (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

    Article  PubMed  CAS  Google Scholar 

  87. Alonso R, Mazzeo C, Rodriguez MC, Marsh M, Fraile-Ramos A, Calvo V, Avila-Flores A, Merida I, Izquierdo M (2011) Diacylglycerol kinase alpha regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. Cell Death Differ 18:1161–1173

    Article  PubMed  CAS  Google Scholar 

  88. Bianco NR, Kim SH, Morelli AE, Robbins PD (2007) Modulation of the immune response using dendritic cell-derived exosomes. Methods Mol Biol 380:443–455

    Article  PubMed  CAS  Google Scholar 

  89. Abusamra AJ, Zhong Z, Zheng X, Li M, Ichim TE, Chin JL, Min WP (2005) Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis. Blood Cells Mol Dis 35:169–173

    Article  PubMed  CAS  Google Scholar 

  90. Pensati L, Costanzo A, Ianni A, Accapezzato D, Iorio R, Natoli G, Nisini R, Almerighi C, Balsano C, Vajro P, Vegnente A, Levrero M (1997) Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis. Gastroenterology 113:1384–1389

    Article  PubMed  CAS  Google Scholar 

  91. Bettinardi A, Brugnoni D, Quiros-Roldan E, Malagoli A, La Grutta S, Correra A, Notarangelo LD (1997) Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis. Blood 89:902–909

    PubMed  CAS  Google Scholar 

  92. Infante AJ, Britton HA, DeNapoli T, Middelton LA, Lenardo MJ, Jackson CE, Wang J, Fleisher T, Straus SE, Puck JM (1998) The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis. J Pediatr 133:629–633

    Article  PubMed  CAS  Google Scholar 

  93. Vaishnaw AK, Orlinick JR, Chu JL, Krammer PH, Chao MV, Elkon KB (1999) The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations. J Clin Invest 103:355–363

    Article  PubMed  CAS  Google Scholar 

  94. Peters AM, Kohfink B, Martin H, Griesinger F, Wormann B, Gahr M, Roesler J (1999) Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome T-cell lymphoma, and Hodgkin’s disease. Exp Hematol 27:868–874

    Article  PubMed  CAS  Google Scholar 

  95. van Den Berg A, Maggio E, Diepstra A, de Jong D, van Krieken J, Poppema S (2002) Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma. Blood 99:1492–1494

    Article  Google Scholar 

  96. Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM, Blanche S, Bartunkova J, Vilmer E, Fischer A, Le Deist F, Rieux-Laucat F (2004) Autoimmune lymphoproliferative syndrome with somatic Fas mutations. N Engl J Med 351:1409–1418

    Article  PubMed  CAS  Google Scholar 

  97. Del-Rey MJ, Manzanares J, Bosque A, Aguilo JI, Gomez-Rial J, Roldan E, Serrano A, Anel A, Paz-Artal E, Allende LM (2007) Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation. Immunobiology 212:73–83

    Article  PubMed  CAS  Google Scholar 

  98. Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB, Puck JM, Jaffe ES, Pittaluga S, Cohen JI, Fleisher TA, Rao VK (2010) Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood 115:5164–5169

    Article  PubMed  CAS  Google Scholar 

  99. Landowski TH, Qu N, Buyuksal I, Painter JS, Dalton WS (1997) Mutations in the Fas antigen in patients with multiple myeloma. Blood 90:4266–4270

    PubMed  CAS  Google Scholar 

  100. Gronbaek K, Straten PT, Ralfkiaer E, Ahrenkiel V, Andersen MK, Hansen NE, Zeuthen J, Hou-Jensen K, Guldberg P (1998) Somatic Fas mutations in non-Hodgkin’s lymphoma: association with extranodal disease and autoimmunity. Blood 92:3018–3024

    PubMed  CAS  Google Scholar 

  101. Maeda T, Yamada Y, Moriuchi R, Sugahara K, Tsuruda K, Joh T, Atogami S, Tsukasaki K, Tomonaga M, Kamihira S (1999) Fas gene mutation in the progression of adult T cell leukemia. J Exp Med 189:1063–1071

    Article  PubMed  CAS  Google Scholar 

  102. Shin MS, Park WS, Kim SY, Kim HS, Kang SJ, Song KY, Park JY, Dong SM, Pi JH, Oh RR, Lee JY, Yoo NJ, Lee SH (1999) Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma. Am J Pathol 154:1785–1791

    Article  PubMed  CAS  Google Scholar 

  103. Lee SH, Shin MS, Park WS, Kim SY, Dong SM, Pi JH, Lee HK, Kim HS, Jang JJ, Kim CS, Kim SH, Lee JY, Yoo NJ (1999) Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res 59:3068–3072

    PubMed  CAS  Google Scholar 

  104. Muschen M, Re D, Brauninger A, Wolf J, Hansmann ML, Diehl V, Kuppers R, Rajewsky K (2000) Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Res 60:5640–5643

    PubMed  CAS  Google Scholar 

  105. Lee SH, Shin MS, Kim HS, Park WS, Kim SY, Jang JJ, Rhim KJ, Jang J, Lee HK, Park JY, Oh RR, Han SY, Lee JH, Lee JY, Yoo NJ (2000) Somatic mutations of Fas (Apo-1/CD95) gene in cutaneous squamous cell carcinoma arising from a burn scar. J Invest Dermatol 114:122–126

    Article  PubMed  CAS  Google Scholar 

  106. Takakuwa T, Dong Z, Takayama H, Matsuzuka F, Nagata S, Aozasa K (2001) Frequent mutations of Fas gene in thyroid lymphoma. Cancer Res 61:1382–1385

    PubMed  CAS  Google Scholar 

  107. Seeberger H, Starostik P, Schwarz S, Knorr C, Kalla J, Ott G, Muller-Hermelink HK, Greiner A (2001) Loss of Fas (CD95/APO-1) regulatory function is an important step in early MALT-type lymphoma development. Lab Invest 81:977–986

    Article  PubMed  CAS  Google Scholar 

  108. Takayama H, Takakuwa T, Dong Z, Nonomura N, Okuyama A, Nagata S, Aozasa K (2001) Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens. Lab Invest 81:283–288

    Article  PubMed  CAS  Google Scholar 

  109. Park WS, Oh RR, Kim YS, Park JY, Lee SH, Shin MS, Kim SY, Kim PJ, Lee HK, Yoo NY, Lee JY (2001) Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer. J Pathol 193:162–168

    Article  PubMed  CAS  Google Scholar 

  110. Takayama H, Takakuwa T, Tsujimoto Y, Tani Y, Nonomura N, Okuyama A, Nagata S, Aozasa K (2002) Frequent Fas gene mutations in testicular germ cell tumors. Am J Pathol 161:635–641

    Article  PubMed  CAS  Google Scholar 

  111. Dereure O, Levi E, Vonderheid EC, Kadin ME (2002) Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin. J Invest Dermatol 118:949–956

    Article  PubMed  CAS  Google Scholar 

  112. Takakuwa T, Dong Z, Nakatsuka S, Kojya S, Harabuchi Y, Yang WI, Nagata S, Aozasa K (2002) Frequent mutations of Fas gene in nasal NK/T cell lymphoma. Oncogene 21:4702–4705

    Article  PubMed  CAS  Google Scholar 

  113. Shin MS, Kim HS, Lee SH, Lee JW, Song YH, Kim YS, Park WS, Kim SY, Lee SN, Park JY, Lee JH, Xiao W, Jo KH, Wang YP, Lee KY, Park YG, Kim SH, Lee JY, Yoo NJ (2002) Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer. Oncogene 21:4129–4136

    Article  PubMed  CAS  Google Scholar 

  114. Wohlfart S, Sebinger D, Gruber P, Buch J, Polgar D, Krupitza G, Rosner M, Hengstschlager M, Raderer M, Chott A, Mullauer L (2004) FAS (CD95) mutations are rare in gastric MALT lymphoma but occur more frequently in primary gastric diffuse large B-cell lymphoma. Am J Pathol 164:1081–1089

    Article  PubMed  CAS  Google Scholar 

  115. Scholl V, Stefanoff CG, Hassan R, Spector N, Renault IZ (2007) Mutations within the 5′ region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma. Leuk Lymphoma 48:957–963

    Article  PubMed  CAS  Google Scholar 

  116. Wu J, Xie F, Qian K, Gibson AW, Edberg JC, Kimberly RP (2011) FAS mRNA editing in human systemic lupus erythematosus. Hum Mutat 32:1268–1277

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Grants from ANR (JC07_183182), INCa (projets libres recherche biomédicale), Région Bretagne, Rennes Métropole and Ligue Contre le Cancer (Comités d’Ille-et-Vilaine, Comité du Morbihan, Comités de la Dordogne, Comités des Pyrénées-Atlantiques). S.T. is supported by Ligue Contre le Cancer (postdoctoral fellowships).

Author information

Authors and Affiliations

  1. Université Rennes-1, 2 Avenue du Professeur Léon Bernard, 35043, Rennes, France

    Sébastien Tauzin

  2. IRSET, Team “Death Receptors and Tumor Escape”, 2 Av du Prof. Léon Bernard, 35043, Rennes, France

    Laure Debure

  3. Université de Bordeaux-2, UMR CNRS 5164, 146 rue Léo Saignat, 33076, Bordeaux, France

    Jean-François Moreau

  4. University of Rennes-1, IRSET (Institut de Recherche sur la Santé l’Environnement et le Travail), Team “Death Receptors and Tumor Escape”, 2 av Prof Léon Bernard, 35043, Rennes cedex, France

    Patrick Legembre

Authors
  1. Sébastien Tauzin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laure Debure
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-François Moreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick Legembre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Legembre.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tauzin, S., Debure, L., Moreau, JF. et al. CD95-mediated cell signaling in cancer: mutations and post-translational modulations. Cell. Mol. Life Sci. 69, 1261–1277 (2012). https://doi.org/10.1007/s00018-011-0866-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0866-4

Keywords

Search

Navigation