Abstract
Membrane lipid rafts are highly ordered membrane domains enriched in cholesterol, sphingolipids and gangliosides that have the property to segregate and concentrate proteins. Lipid and protein composition of lipid rafts differs from that of the surrounding membrane, thus providing sorting platforms and hubs for signal transduction molecules, including CD95 death receptor-mediated signaling. CD95 can be recruited to rafts in a reversible way through S-palmitoylation following activation of cells with its physiological cognate ligand as well as with a wide variety of inducers, including several antitumor drugs through ligand-independent intracellular mechanisms. CD95 translocation to rafts can be modulated pharmacologically, thus becoming a target for the treatment of apoptosis-defective diseases, such as cancer. CD95-mediated signaling largely depends on protein–protein interactions, and the recruitment and concentration of CD95 and distinct downstream apoptotic molecules in membrane raft domains, forming raft-based supramolecular entities that act as hubs for apoptotic signaling molecules, favors the generation and amplification of apoptotic signals. Efficient CD95-mediated apoptosis involves CD95 and raft internalization, as well as the involvement of different subcellular organelles. In this review, we briefly summarize and discuss the involvement of lipid rafts in the regulation of CD95-mediated apoptosis that may provide a new avenue for cancer therapy.
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Joliot A, Prochiantz A (2004) Transduction peptides: from technology to physiology. Nat Cell Biol 6:189–196
Koren E, Torchilin VP (2012) Cell-penetrating peptides: breaking through to the other side. Trends Mol Med 18:385–393
Bechara C, Sagan S (2013) Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett 587:1693–1702
Wang F, Wang Y, Zhang X, Zhang W, Guo S, Jin F (2014) Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery. J Control Release 174:126–136
Farkhani SM, Valizadeh A, Karami H, Mohammadi S, Sohrabi N, Badrzadeh F (2014) Cell penetrating peptides: efficient vectors for delivery of nanoparticles, nanocarriers, therapeutic and diagnostic molecules. Peptides 57:78–94
Richard JP, Melikov K, Vives E et al (2003) Cell-penetrating peptides. A reevaluation of the mechanism of cellular uptake. J Biol Chem 278:585–590
Verdurmen WP, Thanos M, Ruttekolk IR, Gulbins E, Brock R (2010) Cationic cell-penetrating peptides induce ceramide formation via acid sphingomyelinase: implications for uptake. J Control Release 147:171–179
Guterstam P, Madani F, Hirose H et al (2009) Elucidating cell-penetrating peptide mechanisms of action for membrane interaction, cellular uptake, and translocation utilizing the hydrophobic counter-anion pyrenebutyrate. Biochim Biophys Acta 1788:2509–2517
Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39
Ikonen E (2001) Roles of lipid rafts in membrane transport. Curr Opin Cell Biol 13:470–477
Maxfield FR (2002) Plasma membrane microdomains. Curr Opin Cell Biol 14:483–487
Mollinedo F, Gajate C (2015) Lipid rafts as major platforms for signaling regulation in cancer. Adv Biol Regul 57:130–146
Gajate C, Mollinedo F (2001) The antitumor ether lipid ET-18-OCH3 induces apoptosis through translocation and capping of Fas/CD95 into membrane rafts in human leukemic cells. Blood 98:3860–3863
Hueber AO, Bernard AM, Herincs Z, Couzinet A, He HT (2002) An essential role for membrane rafts in the initiation of Fas/CD95-triggered cell death in mouse thymocytes. EMBO Rep 3:190–196
Grassme H, Cremesti A, Kolesnick R, Gulbins E (2003) Ceramide-mediated clustering is required for CD95-DISC formation. Oncogene 22:5457–5470
Mollinedo F, Gajate C (2006) Fas/CD95 death receptor and lipid rafts: new targets for apoptosis-directed cancer therapy. Drug Resist Updat 9:51–73
Gajate C, Mollinedo F (2011) Lipid rafts and Fas/CD95 signaling in cancer chemotherapy. Recent Pat Anticancer Drug Discov 6:274–283
Gajate C, Mollinedo F (2014) Lipid rafts, endoplasmic reticulum and mitochondria in the antitumor action of the alkylphospholipid analog edelfosine. Anticancer Agents Med Chem 14:509–527
Mollinedo F (2008) Death receptors in multiple myeloma and therapeutic opportunities. In: Lonial S (ed) Myeloma therapy pursuing the plasma cell, chap. 25. Humana Press, Totowa, pp 393–419
Mollinedo F, de la Iglesia-Vicente J, Gajate C et al (2010) Lipid raft-targeted therapy in multiple myeloma. Oncogene 29:3748–3757
Mollinedo F, de la Iglesia-Vicente J, Gajate C et al (2010) In vitro and in vivo selective antitumor activity of Edelfosine against mantle cell lymphoma and chronic lymphocytic leukemia involving lipid rafts. Clin Cancer Res 16:2046–2054
Mollinedo F, Gajate C (2010) Lipid rafts and clusters of apoptotic signaling molecule-enriched rafts in cancer therapy. Future Oncol 6:811–821
Hryniewicz-Jankowska A, Augoff K, Biernatowska A, Podkalicka J, Sikorski AF (2014) Membrane rafts as a novel target in cancer therapy. Biochim Biophys Acta 1845:155–165
Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731
Karnovsky MJ, Kleinfeld AM, Hoover RL, Klausner RD (1982) The concept of lipid domains in membranes. J Cell Biol 94:1–6
Sankaram MB, Thompson TE (1990) Modulation of phospholipid acyl chain order by cholesterol. A solid-state 2H nuclear magnetic resonance study. Biochemistry 29:10676–10684
Sankaram MB, Thompson TE (1990) Interaction of cholesterol with various glycerophospholipids and sphingomyelin. Biochemistry 29:10670–10675
Mesquita RM, Melo E, Thompson TE, Vaz WL (2000) Partitioning of amphiphiles between coexisting ordered and disordered phases in two-phase lipid bilayer membranes. Biophys J 78:3019–3025
Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572
Brown DA, London E (1998) Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14:111–136
Brown DA, London E (2000) Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem 275:17221–17224
Wang TY, Leventis R, Silvius JR (2000) Fluorescence-based evaluation of the partitioning of lipids and lipidated peptides into liquid-ordered lipid microdomains: a model for molecular partitioning into “lipid rafts”. Biophys J 79:919–933
Wang TY, Silvius JR (2000) Different sphingolipids show differential partitioning into sphingolipid/cholesterol-rich domains in lipid bilayers. Biophys J 79:1478–1489
Pike LJ (2006) Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function. J Lipid Res 47:1597–1598
Brown DA, London E (1997) Structure of detergent-resistant membrane domains: does phase separation occur in biological membranes? Biochem Biophys Res Commun 240:1–7
Schroeder RJ, Ahmed SN, Zhu Y, London E, Brown DA (1998) Cholesterol and sphingolipid enhance the Triton X-100 insolubility of glycosylphosphatidylinositol-anchored proteins by promoting the formation of detergent-insoluble ordered membrane domains. J Biol Chem 273:1150–1157
Schuck S, Honsho M, Ekroos K, Shevchenko A, Simons K (2003) Resistance of cell membranes to different detergents. Proc Natl Acad Sci USA 100:5795–5800
Pike LJ (2004) Lipid rafts: heterogeneity on the high seas. Biochem J 378:281–292
George S, Nelson MD, Dollahon N, Bamezai A (2006) A novel approach to examining compositional heterogeneity of detergent-resistant lipid rafts. Immunol Cell Biol 84:192–202
Mishra S, Joshi PG (2007) Lipid raft heterogeneity: an enigma. J Neurochem 103(Suppl 1):135–142
Lingwood D, Kaiser HJ, Levental I, Simons K (2009) Lipid rafts as functional heterogeneity in cell membranes. Biochem Soc Trans 37:955–960
Inokuchi J, Nagafuku M, Ohno I, Suzuki A (2013) Heterogeneity of gangliosides among T cell subsets. Cell Mol Life Sci 70:3067–3075
Munro S (2003) Lipid rafts: elusive or illusive? Cell 115:377–388
Lichtenberg D, Goni FM, Heerklotz H (2005) Detergent-resistant membranes should not be identified with membrane rafts. Trends Biochem Sci 30:430–436
Lingwood D, Simons K (2007) Detergent resistance as a tool in membrane research. Nat Protoc 2:2159–2165
Simons K, Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11:688–699
Heerklotz H (2002) Triton promotes domain formation in lipid raft mixtures. Biophys J 83:2693–2701
Macdonald JL, Pike LJ (2005) A simplified method for the preparation of detergent-free lipid rafts. J Lipid Res 46:1061–1067
Ostrom RS, Insel PA (2006) Methods for the study of signaling molecules in membrane lipid rafts and caveolae. Methods Mol Biol 332:181–191
Shah MB, Sehgal PB (2007) Nondetergent isolation of rafts. Methods Mol Biol 398:21–28
Persaud-Sawin DA, Lightcap S, Harry GJ (2009) Isolation of rafts from mouse brain tissue by a detergent-free method. J Lipid Res 50:759–767
Schon A, Freire E (1989) Thermodynamics of intersubunit interactions in cholera toxin upon binding to the oligosaccharide portion of its cell surface receptor, ganglioside GM1. Biochemistry 28:5019–5024
Harder T, Scheiffele P, Verkade P, Simons K (1998) Lipid domain structure of the plasma membrane revealed by patching of membrane components. J Cell Biol 141:929–942
Klymchenko AS, Kreder R (2014) Fluorescent probes for lipid rafts: from model membranes to living cells. Chem Biol 21:97–113
Gaus K, Gratton E, Kable EP et al (2003) Visualizing lipid structure and raft domains in living cells with two-photon microscopy. Proc Natl Acad Sci USA 100:15554–15559
Sharma P, Varma R, Sarasij RC et al (2004) Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116:577–589
Kusumi A, Koyama-Honda I, Suzuki K (2004) Molecular dynamics and interactions for creation of stimulation-induced stabilized rafts from small unstable steady-state rafts. Traffic 5:213–230
Lenne PF, Wawrezinieck L, Conchonaud F et al (2006) Dynamic molecular confinement in the plasma membrane by microdomains and the cytoskeleton meshwork. EMBO J 25:3245–3256
Marguet D, Lenne PF, Rigneault H, He HT (2006) Dynamics in the plasma membrane: how to combine fluidity and order. EMBO J 25:3446–3457
Pinaud F, Michalet X, Iyer G, Margeat E, Moore HP, Weiss S (2009) Dynamic partitioning of a glycosyl-phosphatidylinositol-anchored protein in glycosphingolipid-rich microdomains imaged by single-quantum dot tracking. Traffic 10:691–712
Vyas N, Goswami D, Manonmani A et al (2008) Nanoscale organization of hedgehog is essential for long-range signaling. Cell 133:1214–1227
Gombos I, Steinbach G, Pomozi I et al (2008) Some new faces of membrane microdomains: a complex confocal fluorescence, differential polarization, and FCS imaging study on live immune cells. Cytometry A 73:220–229
Eggeling C, Ringemann C, Medda R et al (2009) Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457:1159–1162
van Zanten TS, Cambi A, Garcia-Parajo MF (2010) A nanometer scale optical view on the compartmentalization of cell membranes. Biochim Biophys Acta 1798:777–787
Zhong L, Zeng G, Lu X et al (2009) NSOM/QD-based direct visualization of CD3-induced and CD28-enhanced nanospatial coclustering of TCR and coreceptor in nanodomains in T cell activation. PLoS One 4:e5945
He HT, Marguet D (2011) Detecting nanodomains in living cell membrane by fluorescence correlation spectroscopy. Annu Rev Phys Chem 62:417–436
Turner MS, Sens P, Socci ND (2005) Nonequilibrium raftlike membrane domains under continuous recycling. Phys Rev Lett 95:168301
Fan J, Sammalkorpi M, Haataja M (2010) Lipid microdomains: structural correlations, fluctuations, and formation mechanisms. Phys Rev Lett 104:118101
Fan J, Sammalkorpi M, Haataja M (2010) Influence of nonequilibrium lipid transport, membrane compartmentalization, and membrane proteins on the lateral organization of the plasma membrane. Phys Rev E 81:011908
Fan J, Sammalkorpi M, Haataja M (2010) Formation and regulation of lipid microdomains in cell membranes: theory, modeling, and speculation. FEBS Lett 584:1678–1684
Krause MR, Daly TA, Almeida PF, Regen SL (2014) Push-pull mechanism for lipid raft formation. Langmuir 30:3285–3289
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
Liang H, Fesik SW (1997) Three-dimensional structures of proteins involved in programmed cell death. J Mol Biol 274:291–302
Mollinedo F, Gajate C, Martin-Santamaria S, Gago F (2004) ET-18-OCH3 (edelfosine): a selective antitumour lipid targeting apoptosis through intracellular activation of Fas/CD95 death receptor. Curr Med Chem 11:3163–3184
Eimon PM, Kratz E, Varfolomeev E et al (2006) Delineation of the cell-extrinsic apoptosis pathway in the zebrafish. Cell Death Differ 13:1619–1630
Brojatsch J, Naughton J, Adkins HB, Young JA (2000) TVB receptors for cytopathic and noncytopathic subgroups of avian leukosis viruses are functional death receptors. J Virol 74:11490–11494
Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308
Wilson NS, Dixit V, Ashkenazi A (2009) Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol 10:348–355
Kanda H, Igaki T, Kanuka H, Yagi T, Miura M (2002) Wengen, a member of the Drosophila tumor necrosis factor receptor superfamily, is required for Eiger signaling. J Biol Chem 277:28372–28375
Kauppila S, Maaty WS, Chen P et al (2003) Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. Oncogene 22:4860–4867
Igaki T, Kanda H, Okano H, Xu T, Miura M (2011) Eiger and wengen: the Drosophila orthologs of TNF/TNFR. Adv Exp Med Biol 691:45–50
Ruan W, Unsain N, Desbarats J, Fon EA, Barker PA (2013) Wengen, the sole tumour necrosis factor receptor in Drosophila, collaborates with moesin to control photoreceptor axon targeting during development. PLoS One 8:e60091
Sessler T, Healy S, Samali A, Szegezdi E (2013) Structural determinants of DISC function: new insights into death receptor-mediated apoptosis signalling. Pharmacol Ther 140:186–199
Bridgham JT, Wilder JA, Hollocher H, Johnson AL (2003) All in the family: evolutionary and functional relationships among death receptors. Cell Death Differ 10:19–25
Yonehara S, Ishii A, Yonehara M (1989) A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med 169:1747–1756
Yonehara S (2003) To reviews on physiological and pathological roles of cell death. Cell Struct Funct 28:1–2
Trauth BC, Klas C, Peters AM et al (1989) Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 245:301–305
Itoh N, Yonehara S, Ishii A et al (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243
Oehm A, Behrmann I, Falk W 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
Suda T, Takahashi T, Golstein P, Nagata S (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75:1169–1178
Nagata S, Golstein P (1995) The Fas death factor. Science 267:1449–1456
Nagata S (1997) Apoptosis by death factor. Cell 88:355–365
Lanza F, Moretti S, Papa S, Malavasi F, Castoldi G (1994) Report on the fifth international workshop on human leukocyte differentiation antigens, Boston, November 3–7, 1993. Haematologica 79:374–386
Singer NG, Todd RF, Fox DA (1994) Structures on the cell surface. Update from the fifth international workshop on human leukocyte differentiation antigens. Arthritis Rheum 37:1245–1248
Tanaka M, Suda T, Takahashi T, Nagata S (1995) Expression of the functional soluble form of human fas ligand in activated lymphocytes. EMBO J 14:1129–1135
Mason D, Andre P, Bensussan A et al (2001) CD antigens 2001. Immunology 103:401–406
Mason D, Andre P, Bensussan A et al (2002) CD antigens 2002. Blood 99:3877–3880
Itoh N, Nagata S (1993) A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen. J Biol Chem 268:10932–10937
Mollinedo F, Gajate C (2006) FasL-independent activation of Fas. In: Wajant H (ed) Fas signaling, chap. 2. Landes Bioscience and Springer Science, Georgetown, pp 13–27
Papoff G, Hausler P, Eramo A et al (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
Siegel RM, Frederiksen JK, Zacharias DA et al (2000) Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 288:2354–2357
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
Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME (2002) Molecular ordering of the initial signaling events of CD95. Mol Cell Biol 22:207–220
Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512
Boldin MP, Varfolomeev EE, Pancer Z, Mett IL, Camonis JH, Wallach D (1995) A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain. J Biol Chem 270:7795–7798
Boldin MP, Goncharov TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:803–815
Kischkel FC, Hellbardt S, Behrmann I et al (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J 14:5579–5588
Wang L, Yang JK, Kabaleeswaran V 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
Hymowitz SG, Dixit VM (2010) Unleashing cell death: the Fas-FADD complex. Nat Struct Mol Biol 17:1289–1290
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
Shao RG, Cao CX, Nieves-Neira W, Dimanche-Boitrel MT, Solary E, Pommier Y (2001) Activation of the Fas pathway independently of Fas ligand during apoptosis induced by camptothecin in p53 mutant human colon carcinoma cells. Oncogene 20:1852–1859
Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT (1999) Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem 274:7987–7992
Bush JA, Cheung KJ Jr, Li G (2001) Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res 271:305–314
Gajate C, Del Canto-Janez E, Acuna AU et al (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
Gajate C, Fonteriz RI, Cabaner C et al (2000) Intracellular triggering of Fas, independently of FasL, as a new mechanism of antitumor ether lipid-induced apoptosis. Int J Cancer 85:674–682
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
Delmas D, Rebe C, Lacour S 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
Rehemtulla A, Hamilton CA, Chinnaiyan AM, Dixit VM (1997) Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1). J Biol Chem 272:25783–25786
Aragane Y, Kulms D, Metze D et al (1998) Ultraviolet light induces apoptosis via direct activation of CD95 (Fas/APO-1) independently of its ligand CD95L. J Cell Biol 140:171–182
Zhuang S, Kochevar IE (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
Chen Y, Lai MZ (2001) c-Jun NH2-terminal kinase activation leads to a FADD-dependent but Fas ligand-independent cell death in Jurkat T cells. J Biol Chem 276:8350–8357
Fumarola C, Zerbini A, Guidotti GG (2001) Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis. Cell Death Differ 8:1004–1013
Moorman JP, Prayther D, McVay D, Hahn YS, Hahn CS (2003) The C-terminal region of hepatitis C core protein is required for Fas-ligand independent apoptosis in Jurkat cells by facilitating Fas oligomerization. Virology 312:320–329
Kim SG, Jong HS, Kim TY et al (2004) Transforming growth factor-β1 induces apoptosis through Fas ligand-independent activation of the Fas death pathway in human gastric SNU-620 carcinoma cells. Mol Biol Cell 15:420–434
Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM (1999) Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. Proc Natl Acad Sci USA 96:8699–8704
Gajate C, Gonzalez-Camacho F, Mollinedo F (2009) Involvement of raft aggregates enriched in Fas/CD95 death-inducing signaling complex in the antileukemic action of edelfosine in Jurkat cells. PLoS One 4:e5044
Matzke A, Massing U, Krug HF (2001) Killing tumour cells by alkylphosphocholines: evidence for involvement of CD95. Eur J Cell Biol 80:1–10
Bertin J, Armstrong RC, Ottilie S et al (1997) Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA 94:1172–1176
Alderson MR, Armitage RJ, Maraskovsky E et al (1993) Fas transduces activation signals in normal human T lymphocytes. J Exp Med 178:2231–2235
Owen-Schaub LB, Meterissian S, Ford RJ (1993) Fas/APO-1 expression and function on malignant cells of hematologic and nonhematologic origin. J Immunother Emphas Tumor Immunol 14:234–241
Freiberg RA, Spencer DM, Choate KA et al (1997) Fas signal transduction triggers either proliferation or apoptosis in human fibroblasts. J Invest Dermatol 108:215–219
Shinohara H, Yagita H, Ikawa Y, Oyaizu N (2000) Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. Cancer Res 60:1766–1772
Desbarats J, Newell MK (2000) Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6:920–923
Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DE, Palerme JS, Newell MK (2003) Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5:118–125
Sekine C, Yagita H, Kobata T, Hasunuma T, Nishioka K, Okumura K (1996) Fas-mediated stimulation induces IL-8 secretion by rheumatoid arthritis synoviocytes independently of CPP32-mediated apoptosis. Biochem Biophys Res Commun 228:14–20
Imamura R, Konaka K, Matsumoto N et al (2004) Fas ligand induces cell-autonomous NF-kappaB activation and interleukin-8 production by a mechanism distinct from that of tumor necrosis factor-alpha. J Biol Chem 279:46415–46423
Reichmann E (2002) The biological role of the Fas/FasL system during tumor formation and progression. Semin Cancer Biol 12:309–315
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
Legembre P, Schickel R, Barnhart BC, Peter ME (2004) Identification of SNF1/AMP kinase-related kinase as an NF-kappaB-regulated anti-apoptotic kinase involved in CD95-induced motility and invasiveness. J Biol Chem 279:46742–46747
Steller EJ, Borel Rinkes IH, Kranenburg O (2011) How CD95 stimulates invasion. Cell Cycle 10:3857–3862
Wajant H, Pfizenmaier K, Scheurich P (2003) Non-apoptotic Fas signaling. Cytokine Growth Factor Rev 14:53–66
Legembre P, Barnhart BC, Peter ME (2004) The relevance of NF-kappaB for CD95 signaling in tumor cells. Cell Cycle 3:1235–1239
Park SM, Schickel R, Peter ME (2005) Nonapoptotic functions of FADD-binding death receptors and their signaling molecules. Curr Opin Cell Biol 17:610–616
Peter ME, Legembre P, Barnhart BC (2005) Does CD95 have tumor promoting activities? Biochim Biophys Acta 1755:25–36
Kleber S, Sancho-Martinez I, Wiestler B et al (2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13:235–248
Steller EJ, Ritsma L, Raats DA et al (2011) The death receptor CD95 activates the cofilin pathway to stimulate tumour cell invasion. EMBO Rep 12:931–937
Letellier E, Kumar S, Sancho-Martinez I et al (2010) CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site. Immunity 32:240–252
Kang SM, Schneider DB, Lin Z et al (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
Seino K, Kayagaki N, Okumura K, Yagita H (1997) Antitumor effect of locally produced CD95 ligand. Nat Med 3:165–170
Martin-Villalba A, Llorens-Bobadilla E, Wollny D (2013) CD95 in cancer: tool or target? Trends Mol Med 19:329–335
Kavurma MM, Tan NY, Bennett MR (2008) Death receptors and their ligands in atherosclerosis. Arterioscler Thromb Vasc Biol 28:1694–1702
Miyaji M, Jin ZX, Yamaoka S et al (2005) Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis. J Exp Med 202:249–259
Song JH, Tse MC, Bellail A et al (2007) Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells. Cancer Res 67:6946–6955
Parlato S, Giammarioli AM, Logozzi M et al (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
Gajate C, Mollinedo F (2002) Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH3 (Edelfosine), a proapoptotic agent in tumor cells. Curr Drug Metab 3:491–525
Mollinedo F (2007) Antitumor ether lipids: proapoptotic agents with multiple therapeutic indications. Expert Opin Ther Patents 17:385–405
Mollinedo F (2014) Editorial: antitumor alkylphospholipid analogs: a promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment. Anticancer Agents Med Chem 14:495–498
Scheel-Toellner D, Wang K, Singh R et al (2002) The death-inducing signalling complex is recruited to lipid rafts in Fas-induced apoptosis. Biochem Biophys Res Commun 297:876–879
Grassme H, Jekle A, Riehle A et al (2001) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276:20589–20596
Grassme H, Schwarz H, Gulbins E (2001) Molecular mechanisms of ceramide-mediated CD95 clustering. Biochem Biophys Res Commun 284:1016–1030
Paris F, Grassme H, Cremesti A et al (2001) Natural ceramide reverses Fas resistance of acid sphingomyelinase(−/−) hepatocytes. J Biol Chem 276:8297–8305
Cremesti A, Paris F, Grassme H et al (2001) Ceramide enables fas to cap and kill. J Biol Chem 276:23954–23961
Kolesnick R (2002) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest 110:3–8
Prinetti A, Chigorno V, Prioni S et al (2001) Changes in the lipid turnover, composition, and organization, as sphingolipid-enriched membrane domains, in rat cerebellar granule cells developing in vitro. J Biol Chem 276:21136–21145
Cremesti AE, Goni FM, Kolesnick R (2002) Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Lett 531:47–53
Chiantia S, Ries J, Chwastek G et al (2008) Role of ceramide in membrane protein organization investigated by combined AFM and FCS. Biochim Biophys Acta 1778:1356–1364
Castro BM, de Almeida RF, Goormaghtigh E, Fedorov A, Prieto M (2011) Organization and dynamics of Fas transmembrane domain in raft membranes and modulation by ceramide. Biophys J 101:1632–1641
Lacour S, Hammann A, Grazide S et al (2004) Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res 64:3593–3598
Reis-Sobreiro M, Gajate C, Mollinedo F (2009) Involvement of mitochondria and recruitment of Fas/CD95 signaling in lipid rafts in resveratrol-mediated antimyeloma and antileukemia actions. Oncogene 28:3221–3234
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
Stel AJ, Ten Cate B, Jacobs S et al (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
Xu ZX, Ding T, Haridas V, Connolly F, Gutterman JU (2009) Avicin D, a plant triterpenoid, induces cell apoptosis by recruitment of Fas and downstream signaling molecules into lipid rafts. PLoS One 4:e8532
Bodmer JL, Holler N, Reynard S et al (2000) TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol 2:241–243
Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A (2000) Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 12:611–620
Sprick MR, Weigand MA, Rieser E et al (2000) FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12:599–609
Delmas D, Rebe C, Micheau O et al (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
Legembre P, Daburon S, Moreau P et al (2005) Amplification of Fas-mediated apoptosis in type II cells via microdomain recruitment. Mol Cell Biol 25:6811–6820
Gniadecki R (2004) Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis. Biochem Biophys Res Commun 320:165–169
Bionda C, Athias A, Poncet D et al (2008) Differential regulation of cell death in head and neck cell carcinoma through alteration of cholesterol levels in lipid rafts microdomains. Biochem Pharmacol 75:761–772
Yi JS, Choo HJ, Cho BR et al (2009) Ginsenoside Rh2 induces ligand-independent Fas activation via lipid raft disruption. Biochem Biophys Res Commun 385:154–159
Park EK, Lee EJ, Lee SH et al (2010) Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt. Br J Pharmacol 160:1212–1223
Varadhachary AS, Peter ME, Perdow SN, Krammer PH, Salgame P (1999) Selective up-regulation of phosphatidylinositol 3′-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: a mechanism for Th2 resistance from Fas-mediated apoptosis. J Immunol 163:4772–4779
Varadhachary AS, Edidin M, Hanlon AM, Peter ME, Krammer PH, Salgame P (2001) Phosphatidylinositol 3′-kinase blocks CD95 aggregation and caspase-8 cleavage at the death-inducing signaling complex by modulating lateral diffusion of CD95. J Immunol 166:6564–6569
Beneteau M, Pizon M, Chaigne-Delalande B 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
Courtney KD, Corcoran RB, Engelman JA (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28:1075–1083
Shukla S, Maclennan GT, Hartman DJ, Fu P, Resnick MI, Gupta S (2007) Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer 121:1424–1432
Gao X, Lowry PR, Zhou X et al (2011) PI3K/Akt signaling requires spatial compartmentalization in plasma membrane microdomains. Proc Natl Acad Sci USA 108:14509–14514
Zhuang L, Lin J, Lu ML, Solomon KR, Freeman MR (2002) Cholesterol-rich lipid rafts mediate akt-regulated survival in prostate cancer cells. Cancer Res 62:2227–2231
Adam RM, Mukhopadhyay NK, Kim J et al (2007) Cholesterol sensitivity of endogenous and myristoylated Akt. Cancer Res 67:6238–6246
Gao X, Zhang J (2008) Spatiotemporal analysis of differential Akt regulation in plasma membrane microdomains. Mol Biol Cell 19:4366–4373
Gao X, Zhang J (2009) Akt signaling dynamics in plasma membrane microdomains visualized by FRET-based reporters. Commun Integr Biol 2:32–34
Reis-Sobreiro M, Roue G, Moros A et al (2013) Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma. Blood Cancer J 3:e118
Rudelius M, Pittaluga S, Nishizuka S et al (2006) Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood 108:1668–1676
Dal Col J, Zancai P, Terrin L et al (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 111:5142–5151
Gandhavadi M, Allende D, Vidal A, Simon SA, McIntosh TJ (2002) Structure, composition, and peptide binding properties of detergent soluble bilayers and detergent resistant rafts. Biophys J 82:1469–1482
Mannock DA, McIntosh TJ, Jiang X, Covey DF, McElhaney RN (2003) Effects of natural and enantiomeric cholesterol on the thermotropic phase behavior and structure of egg sphingomyelin bilayer membranes. Biophys J 84:1038–1046
Chakrabandhu K, Herincs Z, Huault S et al (2007) Palmitoylation is required for efficient Fas cell death signaling. EMBO J 26:209–220
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
Eramo A, Sargiacomo M, Ricci-Vitiani L 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
Lee KH, Feig C, Tchikov V et al (2006) The role of receptor internalization in CD95 signaling. EMBO J 25:1009–1023
Guicciardi ME, Gores GJ (2009) Life and death by death receptors. FASEB J 23:1625–1637
Kamitani T, Nguyen HP, Yeh ET (1997) Activation-induced aggregation and processing of the human Fas antigen. Detection with cytoplasmic domain-specific antibodies. J Biol Chem 272:22307–22314
Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (2002) The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling. Biochim Biophys Acta 1589:140–150
Resh MD (2004) Membrane targeting of lipid modified signal transduction proteins. Subcell Biochem 37:217–232
Basso AD, Kirschmeier P, Bishop WR (2006) Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res 47:15–31
Greaves J, Chamberlain LH (2007) Palmitoylation-dependent protein sorting. J Cell Biol 176:249–254
Aicart-Ramos C, Valero RA, Rodriguez-Crespo I (2011) Protein palmitoylation and subcellular trafficking. Biochim Biophys Acta 1808:2981–2994
Levental I, Lingwood D, Grzybek M, Coskun U, Simons K (2010) Palmitoylation regulates raft affinity for the majority of integral raft proteins. Proc Natl Acad Sci USA 107:22050–22054
Rossin A, Durivault J, Chakhtoura-Feghali T, Lounnas N, Gagnoux-Palacios L, Hueber AO (2014) Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability. Cell Death Differ. doi:10.1038/cdd.2014.153
Rossin A, Kral R, Lounnas N et al (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
Leon-Bollotte L, Subramaniam S, Cauvard O et al (2011) S-nitrosylation of the death receptor Fas promotes Fas ligand-mediated apoptosis in cancer cells. Gastroenterology 140(2009–2018):e2001–e2004
Cahuzac N, Baum W, Kirkin V et al (2006) Fas ligand is localized to membrane rafts, where it displays increased cell death-inducing activity. Blood 107:2384–2391
Guardiola-Serrano F, Rossin A, Cahuzac N et al (2010) Palmitoylation of human FasL modulates its cell death-inducing function. Cell Death Dis 1:e88
Rossin A, Derouet M, Abdel-Sater F, Hueber AO (2009) Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling. Biochem J 419:185–192
Siegel RM, Martin DA, Zheng L et al (1998) Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis. J Cell Biol 141:1243–1253
Perez D, White E (1998) E1B 19K inhibits Fas-mediated apoptosis through FADD-dependent sequestration of FLICE. J Cell Biol 141:1255–1266
Tang D, Lahti JM, Grenet J, Kidd VJ (1999) Cycloheximide-induced T-cell death is mediated by a Fas-associated death domain-dependent mechanism. J Biol Chem 274:7245–7252
Siegel RM, Muppidi JR, Sarker M et al (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
Schutze S, Tchikov V, Schneider-Brachert W (2008) Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nat Rev Mol Cell Biol 9:655–662
Caulin C, Ware CF, Magin TM, Oshima RG (2000) Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. J Cell Biol 149:17–22
Gilbert S, Loranger A, Daigle N, Marceau N (2001) Simple epithelium keratins 8 and 18 provide resistance to Fas-mediated apoptosis. The protection occurs through a receptor-targeting modulation. J Cell Biol 154:763–773
Inada H, Izawa I, Nishizawa M et al (2001) Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD. J Cell Biol 155:415–426
Ku NO, Soetikno RM, Omary MB (2003) Keratin mutation in transgenic mice predisposes to Fas but not TNF-induced apoptosis and massive liver injury. Hepatology 37:1006–1014
Gilbert S, Loranger A, Lavoie JN, Marceau N (2012) Cytoskeleton keratin regulation of FasR signaling through modulation of actin/ezrin interplay at lipid rafts in hepatocytes. Apoptosis 17:880–894
Jiang S, Zhao L, Lu Y et al (2014) Piwil2 inhibits keratin 8 degradation through promoting p38-induced phosphorylation to resist Fas-mediated apoptosis. Mol Cell Biol 34:3928–3938
Schutte B, Henfling M, Kolgen W et al (2004) Keratin 8/18 breakdown and reorganization during apoptosis. Exp Cell Res 297:11–26
Weerasinghe SV, Ku NO, Altshuler PJ, Kwan R, Omary MB (2014) Mutation of caspase-digestion sites in keratin 18 interferes with filament reorganization, and predisposes to hepatocyte necrosis and loss of membrane integrity. J Cell Sci 127:1464–1475
Lee J, Jang KH, Kim H et al (2013) Predisposition to apoptosis in keratin 8-null liver is related to inactivation of NF-kappaB and SAPKs but not decreased c-Flip. Biol Open 2:695–702
Fortier AM, Asselin E, Cadrin M (2013) Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation. J Biol Chem 288:11555–11571
Lee JC, Schickling O, Stegh AH et al (2002) DEDD regulates degradation of intermediate filaments during apoptosis. J Cell Biol 158:1051–1066
Dinsdale D, Lee JC, Dewson G, Cohen GM, Peter ME (2004) Intermediate filaments control the intracellular distribution of caspases during apoptosis. Am J Pathol 164:395–407
Schutte B, Henfling M, Ramaekers FC (2006) DEDD association with cytokeratin filaments correlates with sensitivity to apoptosis. Apoptosis 11:1561–1572
Gajate C, Gonzalez-Camacho F, Mollinedo F (2009) Lipid raft connection between extrinsic and intrinsic apoptotic pathways. Biochem Biophys Res Commun 380:780–784
Mollinedo F, Gajate C (2010) Lipid rafts, death receptors and CASMERs: new insights for cancer therapy. Future Oncol 6:491–494
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490
Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501
Nieto-Miguel T, Gajate C, Gonzalez-Camacho F, Mollinedo F (2008) Proapoptotic role of Hsp90 by its interaction with c-Jun N-terminal kinase in lipid rafts in edelfosine-mediated antileukemic therapy. Oncogene 27:1779–1787
Gajate C, Santos-Beneit A, Modolell M, Mollinedo F (1998) Involvement of c-Jun NH2-terminal kinase activation and c-Jun in the induction of apoptosis by the ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine. Mol Pharmacol 53:602–612
Fouque A, Debure L, Legembre P (2014) The CD95/CD95L signaling pathway: a role in carcinogenesis. Biochim Biophys Acta 1846:130–141
Wajant H (2014) Principles and mechanisms of CD95 activation. Biol Chem 395:1401–1416
Kataoka T, Budd RC, Holler N et al (2000) The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10:640–648
Gupta S (2003) Molecular signaling in death receptor and mitochondrial pathways of apoptosis (Review). Int J Oncol 22:15–20
Kataoka T (2005) The caspase-8 modulator c-FLIP. Crit Rev Immunol 25:31–58
Safa AR (2012) c-FLIP, a master anti-apoptotic regulator. Exp Oncol 34:176–184
Collins C, Wolfe J, Roessner K, Shi C, Sigal LH, Budd RC (2005) Lyme arthritis synovial gammadelta T cells instruct dendritic cells via fas ligand. J Immunol 175:5656–5665
Engedal N, Blomhoff HK (2003) Combined action of ERK and NF kappa B mediates the protective effect of phorbol ester on Fas-induced apoptosis in Jurkat cells. J Biol Chem 278:10934–10941
Siegmund D, Klose S, Zhou D et al (2007) Role of caspases in CD95L- and TRAIL-induced non-apoptotic signalling in pancreatic tumour cells. Cell Signal 19:1172–1184
Lee SM, Kim EJ, Suk K, Lee WH (2011) Stimulation of Fas (CD95) induces production of pro-inflammatory mediators through ERK/JNK-dependent activation of NF-kappaB in THP-1 cells. Cell Immunol 271:157–162
Mahfoud R, Garmy N, Maresca M, Yahi N, Puigserver A, Fantini J (2002) Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins. J Biol Chem 277:11292–11296
Chakrabandhu K, Huault S, Garmy N et al (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
Ruan W, Lee CT, 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
Kuo WC, Yang KT, Hsieh SL, Lai MZ (2010) Ezrin is a negative regulator of death receptor-induced apoptosis. Oncogene 29:1374–1383
Doma E, Chakrabandhu K, Hueber AO (2010) A novel role of microtubular cytoskeleton in the dynamics of caspase-dependent Fas/CD95 death receptor complexes during apoptosis. FEBS Lett 584:1033–1040
Sorice M, Matarrese P, Tinari A et al (2009) Raft component GD3 associates with tubulin following CD95/Fas ligation. Faseb J 23:3298–3308
Sorice M, Matarrese P, Manganelli V et al (2010) Role of GD3-CLIPR-59 association in lymphoblastoid T cell apoptosis triggered by CD95/Fas. PLoS One 5:e8567
Perez F, Pernet-Gallay K, Nizak C, Goodson HV, Kreis TE, Goud B (2002) CLIPR-59, a new trans-Golgi/TGN cytoplasmic linker protein belonging to the CLIP-170 family. J Cell Biol 156:631–642
Lallemand-Breitenbach V, Quesnoit M, Braun V et al (2004) CLIPR-59 is a lipid raft-associated protein containing a cytoskeleton-associated protein glycine-rich domain (CAP-Gly) that perturbs microtubule dynamics. J Biol Chem 279:41168–41178
Koncz G, Kerekes K, Chakrabandhu K, Hueber AO (2008) Regulating Vav1 phosphorylation by the SHP-1 tyrosine phosphatase is a fine-tuning mechanism for the negative regulation of DISC formation and Fas-mediated cell death signaling. Cell Death Differ 15:494–503
Hebert M, Potin S, Sebbagh M, Bertoglio J, Breard J, Hamelin J (2008) Rho-ROCK-dependent ezrin-radixin-moesin phosphorylation regulates Fas-mediated apoptosis in Jurkat cells. J Immunol 181:5963–5973
Lozupone F, Lugini L, Matarrese P et al (2004) Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J Biol Chem 279:9199–9207
Soderstrom TS, Nyberg SD, Eriksson JE (2005) CD95 capping is ROCK-dependent and dispensable for apoptosis. J Cell Sci 118:2211–2223
Stamenkovic I, Yu Q (2010) Merlin, a “magic” linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci 11:471–484
Stickney JT, Bacon WC, Rojas M, Ratner N, Ip W (2004) Activation of the tumor suppressor merlin modulates its interaction with lipid rafts. Cancer Res 64:2717–2724
Piazzolla D, Meissl K, Kucerova L, Rubiolo C, Baccarini M (2005) Raf-1 sets the threshold of Fas sensitivity by modulating Rok-alpha signaling. J Cell Biol 171:1013–1022
Ehrenreiter K, Piazzolla D, Velamoor V et al (2005) Raf-1 regulates Rho signaling and cell migration. J Cell Biol 168:955–964
Garofalo T, Giammarioli AM, Misasi R et al (2005) Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells. Cell Death Differ 12:1378–1389
Matarrese P, Manganelli V, Garofalo T et al (2008) Endosomal compartment contributes to the propagation of CD95/Fas-mediated signals in type II cells. Biochem J 413:467–478
Malorni W, Giammarioli AM, Garofalo T, Sorice M (2007) Dynamics of lipid raft components during lymphocyte apoptosis: the paradigmatic role of GD3. Apoptosis 12:941–949
Sorice M, Garofalo T, Misasi R, Manganelli V, Vona R, Malorni W (2012) Ganglioside GD3 as a raft component in cell death regulation. Anticancer Agents Med Chem 12:376–382
Ren W, Sun Y, Du K (2013) DHHC17 palmitoylates ClipR-59 and modulates ClipR-59 association with the plasma membrane. Mol Cell Biol 33:4255–4265
Ausili A, Torrecillas A, Aranda FJ et al (2008) Edelfosine is incorporated into rafts and alters their organization. J Phys Chem B 112:11643–11654
Cuesta-Marban A, Botet J, Czyz O et al (2013) Drug uptake, lipid rafts, and vesicle trafficking modulate resistance to an anticancer lysophosphatidylcholine analogue in yeast. J Biol Chem 288:8405–8418
van der Luit AH, Budde M, Ruurs P, Verheij M, van Blitterswijk WJ (2002) Alkyl-lysophospholipid accumulates in lipid rafts and induces apoptosis via raft-dependent endocytosis and inhibition of phosphatidylcholine synthesis. J Biol Chem 277:39541–39547
Van Der Luit AH, Budde M, Verheij M, Van Blitterswijk WJ (2003) Different modes of internalization of apoptotic alkyl-lysophospholipid and cell-rescuing lysophosphatidylcholine. Biochem J 374:747–753
van der Luit AH, Vink SR, Klarenbeek JB et al (2007) A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther 6:2337–2345
Zaremberg V, Gajate C, Cacharro LM, Mollinedo F, McMaster CR (2005) Cytotoxicity of an anti-cancer lysophospholipid through selective modification of lipid raft composition. J Biol Chem 280:38047–38058
Busto JV, del Canto-Jañez E, Goñi FM, Mollinedo F, Alonso A (2008) Combination of the anti-tumour cell ether lipid edelfosine with sterols abolishes haemolytic side effects of the drug. J Chem Biol 1:89–94
Gajate C, Matos-da-Silva M, Dakir EL, Fonteriz RI, Alvarez J, Mollinedo F (2012) Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum. Oncogene 31:2627–2639
Nieto-Miguel T, Gajate C, Mollinedo F (2006) Differential targets and subcellular localization of antitumor alkyl-lysophospholipid in leukemic versus solid tumor cells. J Biol Chem 281:14833–14840
Mollinedo F, Fernandez M, Hornillos V et al (2011) Involvement of lipid rafts in the localization and dysfunction effect of the antitumor ether phospholipid edelfosine in mitochondria. Cell Death Dis 2:e158
Gajate C, Santos-Beneit AM, Macho A et al (2000) Involvement of mitochondria and caspase-3 in ET-18-OCH3-induced apoptosis of human leukemic cells. Int J Cancer 86:208–218
Mollinedo F, Fernandez-Luna JL, Gajate C et al (1997) Selective induction of apoptosis in cancer cells by the ether lipid ET-18-OCH3 (Edelfosine): molecular structure requirements, cellular uptake, and protection by Bcl-2 and Bcl-XL. Cancer Res 57:1320–1328
de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610
Kornmann B, Currie E, Collins SR et al (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325:477–481
Kornmann B, Walter P (2010) ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology. J Cell Sci 123:1389–1393
Osman C, Voelker DR, Langer T (2011) Making heads or tails of phospholipids in mitochondria. J Cell Biol 192:7–16
Pizon M, Rampanarivo H, Tauzin S et al (2011) Actin-independent exclusion of CD95 by PI3K/AKT signalling: implications for apoptosis. Eur J Immunol 41:2368–2378
DeMorrow S, Glaser S, Francis H et al (2007) Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts. J Biol Chem 282:13098–13113
Elyassaki W, Wu S (2006) Lipid rafts mediate ultraviolet light-induced Fas aggregation in M624 melanoma cells. Photochem Photobiol 82:787–792
Acknowledgments
The studies from our laboratory were supported by grants from Spanish Ministerio de Economia y Competitividad (SAF2011-30518; and RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), European Community’s Seventh Framework Programme FP7-2007-2013 (Grant HEALTH-F2-2011-256986, PANACREAS), and Junta de Castilla y León (CSI052A11-2 and CSI221A12-2).
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Gajate, C., Mollinedo, F. Lipid rafts and raft-mediated supramolecular entities in the regulation of CD95 death receptor apoptotic signaling. Apoptosis 20, 584–606 (2015). https://doi.org/10.1007/s10495-015-1104-6
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DOI: https://doi.org/10.1007/s10495-015-1104-6