FAS (Fas cell surface death receptor)

2014-11-01   Doriane Sanséau , Patrick Legembre 


Atlas Image
Gene localisation: CD95 gene spans approximately 25 kb on human chromosome 10.


CD95 (also known as Fas) is a death receptor that belongs to the TNF-receptor superfamily. Expressed at the cell surface as a homotrimer, this receptor implements both apoptotic and non-apoptotic signalling pathways. While the apoptotic signalling pathway is involved in tumor surveillance, peripheral tolerance and immune homeostasis (Strasser et al., 2009), its non-apoptotic cues seem to promote oncogenesis (Chen et al., 2010; Hoogwater et al., 2010; Kleber et al., 2010; Malleter et al., 2013; Steller et al., 2011).



Gene annotation is APT1.
Atlas Image
According to Ensembl, CD95 gene is composed of 9 exons encoding 3 variants.


CD95 gene is composed of 9 exons.


According to Ensembl, the gene has 18 transcripts (splice variants). Among them, three transcripts encode for proteins (represented in the diagram). Variant 1 encodes for the longest protein of 335 aa. Variant 2 encodes for a CD95 protein lacking transmembrane region (exon 6) and thus corresponding to a soluble receptor. Variant 3 contains a distinct and shorter c-terminus compare to variant 1 and encodes for a protein of 220 aa.


No known pseudogenes.



Type I transmembrane protein.
Atlas Image
CD95 is a 335 amino acids type 1 transmembrane glycoprotein. Signal peptide corresponds to amino acid 1 to 16 (Itoh et al., 1991). The PLAD (pre-ligand assembly domain) and the CRDs (cysteine-rich domain) are encoded by exon 2 to 5. Exon 6 encompasses the transmembrane domain (TM), and the CD95 intracellular region consists in exons 7 to 9. The FAS DD is encoded by exon 9.


CD95 displays two different numberings. While some researchers start to count from the first translated amino acid after methionine (335 aa), others start at the first amino acid after signal peptide (319 aa) (Itoh et al., 1991). CD95 contains three cysteine-rich domains (CRDs). CRD2 and the upper part of CRD3 interact with CD95L (Schneider et al., 1997). CD95 is expressed at the plasma membrane as a pre-associated homotrimer (Siegel et al., 2000) because of homotypic interactions occurring between its pre-ligand assembly domains (PLAD) (amino acids 43 to 66 (Edmond et al., 2014), count starts after signal peptide). The intracellular region of CD95 encompasses an 87-amino-acid-long stretch designated the death domain (DD) whose structure consists of six amphipathic α-helices arranged anti-parallel to one another (Huang et al., 1997). The 15 last amino acids of CD95 exert an inhibitory action on the CD95-mediated apoptotic signal due to the recruitment of the phosphatase FAP1 (Yanagisawa et al., 1997).
Atlas Image
The molecular weight of CD95 varies between 40 to 50 kDa due to different post-translational modifications: glycosylation (Shatnyeva et al., 2011; Keppler et al., 1999), nitrosylation (Leon-Bollotte et al., 2011), S-glutathionylation (Anathy et al., 2009) and palmitoylation (Chakrabandhu et al., 2007; Feig et al., 2007).


CD95 is ubiquitously expressed in human body.


CD95 is mainly found at cell surface. CD95 is retained internalized in cells through a FAP-1-driven mechanism, while its translocation to the cell surface relies on dynamin-2 (Ivanov et al., 2003; Ivanov et al., 2006).


CD95 contributes to immune homeostasis, elimination of transformed and infected cells, and plays a pivotal role in peripheral tolerance. CD95/CD95L pair is also responsible for preventing inflammation in certain tissues designated immune privileged sites, such as eyes and testis. More recently, CD95 has been shown to promote carcinogenesis ((Chen et al., 2010; Hoogwater et al., 2010; Kleber et al., 2010; Malleter et al., 2013; O Reilly et al., 2009).
Upon binding of membrane-bound CD95L to CD95, CD95-DD recruits the adaptor molecule Fas-associated death domain protein (FADD) and caspase-8, leading to caspase activation and apoptosis (Kischkel et al., 1995). The complex CD95/FADD/Caspase-8 is called death-inducing signalling complex (DISC) (Kischkel et al., 1995). DISC formation is regulated by several molecular mechanisms including c-FLIP (FLICE-like-inhibitory-protein) (Irmler et al., 1997), FAP-1 (Fas associated phosphatase 1) (Sato et al., 1995) and PED-PEA15 (Condorelli et al., 1999).
Cells can be divided in two groups with regard to the magnitude of DISC formation, and the role played by the mitochondrion in this pathway (Scaffidi et al., 1998). In type I cells, DISC formation occurs rapidly and efficiently, resulting in the release of a large amount of activated caspase-8 in the cytosol. Whereas, type II cells have difficulties forming this complex, and the amount of active caspase-8 is insufficient to directly activate the effector caspase-3 and caspase-7 (Scaffidi et al., 1998). The low level of activated caspase-8 in type II cells is sufficient to cleave BID, a BH3-only protein, which links the death receptor to the apoptotic activity of mitochondria. Indeed, caspase-8-driven BID truncation generates tBID, which translocates to mitochondria, and triggers the release of pro-apoptotic factors (Yin, 2000; Yin et al., 1999). Type II cells are addicted to this latter signal because they contain higher levels of the caspase-3 inhibitor XIAP than type I cells (Jost et al., 2009). To summarize, DISC formation and IAP amount are two cellular markers that allow a clear discrimination between type I and type II cells.
CD95 engagement also induces non-apoptotic signalling pathways promoting cell motility, invasiveness (Hoogwater et al., 2010; Kleber et al., 2010; Malleter et al., 2013; Steller et al., 2011; Barnhart et al., 2004), inflammation (O Reilly et al., 2009; Audo et al., 2014; Letellier et al., 2010; Tauzin et al., 2011) and organ regeneration (Desbarats et al., 2003; Desbarats and Newell, 2000). Indeed, CD95 can implement NFκB (O Reilly et al., 2009; Barnhart et al., 2004; Wajant et al., 1998), phosphatidylinositol 3-kinase (PI3K) (Kleber et al., 2008;Tauzin et al., 2011) or MAPK signaling pathways (Hoogwater et al., 2010; Desbarats et al., 2003). CD95 has also been reported to play a pivotal role in T cell activation (Akimzhanov et al., 2010; Alderson et al., 1993).
Of note, while interaction of transmembrane CD95L with CD95 triggers cell death, its metalloprotease-cleaved counterpart (cl-CD95L) does not form DISC, but induces the formation of an atypical complex designated motility-inducing signalling complex (MISC)5.


The CD95-mediated apoptotic system is conserved among all mammals. The most primitive invertebrate TNF/TNFR pair has been reported in the fruit fly Drosophila melangastor (Kauppila et al., 2003; Moreno et al., 2002; Collette et al., 2003). However, a more recent study highlighted that TNFSF and TNFRSF members are conserved in more ancient invertebrates such as Cnidaria (Quistad et al., 2014). Moreover, comparison of coral TNFSF/TNFRSF members with proteins from Homo sapiens reveals high genetic and structural conservation.



Most of the mutations are gathered in exons 8 and 9 encoding the CD95 intracellular region. Malignant tumor cells and ALPS type Ia cells harboring a heterozygous mutation inside the CD95-DD, exhibit resistance to the CD95-mediated apoptotic signal, but remain able to elicit non-apoptotic signal such NFkB, MAPK, and PI3K (Legembre et al., 2004). Tree "hot-spots" of mutation (arginine in position 234, aspartic acid in position 244 and valine in position 251) have been identified and implicated in the interaction of CD95/FADD (Tauzin et al., 2012).
Other mutations are reported on different website: COSMIC and LOVD.
Extensive analysis of the loss-of-function CD95 mutations. Mutations reported in Tables 1 and 2 (see below) have been placed in the amino-acid sequence of CD95.


CD95 germinal mutations have been reported in ALPS type Ia.


CD95 somatic mutations have been reported in several cancers.

Implicated in

Hodgkins lymphoma is a cancer of the immune system characterised by the presence of mononucleated Hodgkins cells and multinucleated Reed-Sternberg cell. This disease can be caused by somatic mutation of CD95 (Tables 1 and 2). The symptoms are enlargement of lymph nodes, spleen or other immune tissue. Also non hodgkins lymphoma (NHL) show somatic mutations of CD95 (Tables 1 and 2): thyroid lymphoma, mucosa associated lymphoid tissue-type lymphomas, follicle center lymphomas, mycosis fungoide (cutaneous T cell lymphoma), nasal NK/T cell lymphoma, anaplastic large lymphoma, B-chronic lymphocytic lymphoma, and diffuse large B cells lymphomas. 8% of patients with NHL exhibits autoimmune phenomena (Grønbaek et al., 1995).
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Table1. Germinal mutations in the APT1 gene.
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Table 2. Somatic mutations in the APT1 gene. * Amino acid numbers have been modified according to the regular amino acid annotation. ** Threonine 256 depicted in this study corresponded in fact to amino acid 254.
Entity name
Various cancers
Somatic mutations of CD95 have been also identified in various cancers (Table 2): multiple myelomas, T cell leukemia, cutaneous malignant melanoma, squamous cell carcinoma, bladder carcinoma, prostatic cancer, gastric cancer, testicular germ cell tumor, and non small cell lung cancer.
Entity name
Autoimmune lymphoproliferative syndrome type Ia
ALPS is characterised by chronic lymphadenopathy and splenomegaly, expanded populations of double-negative α/β T lymphocytes (CD3+, CD4-, CD8-). ALPS patients often develop autoimmunity. These patients exhibit germinal mutations in CD95 gene with no or rare "loss of heterozygosity" (Table 1). The ALPS patients show an increased risk to develop Hodgkin and non-Hodgkin lymphomas (Straus et al., 2001).
Entity name
Systemic lupus erythematous
Systemic lupus erythematous is a prototypic systemic autoimmune disorder characterized by autoantibody production, immune complex formation and cell-mediated reactivity against self. CD95/CD95L have been implicated in this disease.


Pubmed IDLast YearTitleAuthors
206969182010T-cell receptor complex is essential for Fas signal transduction.Akimzhanov AM et al
75040621993Fas transduces activation signals in normal human T lymphocytes.Alderson MR et al
191717572009Redox amplification of apoptosis by caspase-dependent cleavage of glutaredoxin 1 and S-glutathionylation of Fas.Anathy V et al
250780972014Distinct effects of soluble and membrane-bound fas ligand on fibroblast-like synoviocytes from rheumatoid arthritis patients.Audo R et al
152723062004CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells.Barnhart BC et al
90283211997Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis.Bettinardi A et al
171599082007Palmitoylation is required for efficient Fas cell death signaling.Chakrabandhu K et al
205057302010CD95 promotes tumour growth.Chen L et al
128605302003A co-evolution perspective of the TNFSF and TNFRSF families in the immune system.Collette Y et al
104426311999PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.Condorelli G et al
173368282007Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a new germline Fas gene mutation.Del-Rey MJ et al
120603882002Infrequent 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.Dereure O et al
125451712003Fas engagement induces neurite growth through ERK activation and p35 upregulation.Desbarats J et al
203604702010Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome.Dowdell KC et al
89293611996Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.Drappa J et al
246326102015Downregulation of ceramide synthase-6 during epithelial-to-mesenchymal transition reduces plasma membrane fluidity and cancer cell motility.Edmond V et al
171599072007Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signaling.Feig C et al
75401171995Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome.Fisher GH et al
97871341998Somatic Fas mutations in non-Hodgkin's lymphoma: association with extranodal disease and autoimmunity.Grønbaek K et al
154593022004Autoimmune lymphoproliferative syndrome with somatic Fas mutations.Holzelova E et al
201881032010Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells.Hoogwater FJ et al
89679521996NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain.Huang B et al
98214191998The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis.Infante AJ et al
92171611997Inhibition of death receptor signals by cellular FLIP.Irmler M et al
17131271991The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.Itoh N et al
127244202003FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.Ivanov VN et al
163060442006Opposite roles of FAP-1 and dynamin in the regulation of Fas (CD95) translocation to the cell surface and susceptibility to Fas ligand-mediated apoptosis.Ivanov VN et al
100908851999Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Jackson CE et al
196260052009XIAP discriminates between type I and type II FAS-induced apoptosis.Jost PJ et al
128942272003Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila.Kauppila S et al
103369881999Differential sialylation of cell surface glycoconjugates in a human B lymphoma cell line regulates susceptibility for CD95 (APO-1/Fas)-mediated apoptosis and for infection by a lymphotropic virus.Keppler OT et al
85218151995Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor.Kischkel FC et al
183284272008Yes and PI3K bind CD95 to signal invasion of glioblastoma.Kleber S et al
93732361997Mutations in the Fas antigen in patients with multiple myeloma.Landowski TH et al
106201272000Somatic mutations of Fas (Apo-1/CD95) gene in cutaneous squamous cell carcinoma arising from a burn scar.Lee SH et al
155146802004Induction of apoptosis and activation of NF-kappaB by CD95 require different signalling thresholds.Legembre P et al
213541492011S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells.Leon-Bollotte L et al
201532212010CD95-ligand on peripheral myeloid cells activates Syk kinase to trigger their recruitment to the inflammatory site.Letellier E et al
101908971999Fas gene mutation in the progression of adult T cell leukemia.Maeda T et al
240727452013CD95L cell surface cleavage triggers a prometastatic signaling pathway in triple-negative breast cancer.Malleter M et al
121763392002Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily.Moreno E et al
110597542000Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells.Müschen M et al
197944942009Membrane-bound Fas ligand only is essential for Fas-induced apoptosis.O' Reilly LA et al
111801612001Somatic mutations in the death domain of the Fas (Apo-1/CD95) gene in gastric cancer.Park WS et al
93225341997Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a patient with type 2 autoimmune hepatitis.Pensati L et al
103404031999Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin's disease.Peters AM et al
249275462014Evolution of TNF-induced apoptosis reveals 550 My of functional conservation.Quistad SD et al
105158601999Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations.Rieux-Laucat F et al
75363431995FAP-1: a protein tyrosine phosphatase that associates with Fas.Sato T et al
95010891998Two CD95 (APO-1/Fas) signaling pathways.Scaffidi C et al
92280581997Characterization of Fas (Apo-1, CD95)-Fas ligand interaction.Schneider P et al
174877402007Mutations within the 5' region of FAS/CD95 gene in nodal diffuse large B-cell lymphoma.Scholl V et al
114549872001Loss of Fas (CD95/APO-1) regulatory function is an important step in early MALT-type lymphoma development.Seeberger H et al
216256442011Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.Shatnyeva OM et al
120376692002Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer.Shin MS et al
103628031999Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma.Shin MS et al
108759182000Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.Siegel RM et al
220645192011How CD95 stimulates invasion.Steller EJ et al
192399022009The many roles of FAS receptor signaling in the immune system.Strasser A et al
114184802001The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.Straus SE et al
120963472002Frequent mutations of Fas gene in nasal NK/T cell lymphoma.Takakuwa T et al
121633882002Frequent Fas gene mutations in testicular germ cell tumors.Takayama H et al
217130322011The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway.Tauzin S et al
220422712012CD95-mediated cell signaling in cancer: mutations and post-translational modulations.Tauzin S et al
99274961999The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations.Vaishnaw AK et al
94276461998Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction.Wajant H et al
149828612004FAS (CD95) mutations are rare in gastric MALT lymphoma but occur more frequently in primary gastric diffuse large B-cell lymphoma.Wohlfart S et al
217931062011FAS mRNA editing in Human Systemic Lupus Erythematosus.Wu J et al
90796831997The molecular interaction of Fas and FAP-1. A tripeptide blocker of human Fas interaction with FAP-1 promotes Fas-induced apoptosis.Yanagisawa J et al
104769691999Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis.Yin XM et al
110321682000Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways.Yin XM et al
118305072002Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma.van den Berg A et al

Other Information

Locus ID:

NCBI: 355
MIM: 134637
HGNC: 11920
Ensembl: ENSG00000026103


dbSNP: 355
ClinVar: 355
TCGA: ENSG00000026103


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
Cytokine-cytokine receptor interactionKEGGko04060
p53 signaling pathwayKEGGko04115
Natural killer cell mediated cytotoxicityKEGGko04650
Type I diabetes mellitusKEGGko04940
Alzheimer's diseaseKEGGko05010
Autoimmune thyroid diseaseKEGGko05320
Allograft rejectionKEGGko05330
Graft-versus-host diseaseKEGGko05332
MAPK signaling pathwayKEGGhsa04010
Cytokine-cytokine receptor interactionKEGGhsa04060
p53 signaling pathwayKEGGhsa04115
Natural killer cell mediated cytotoxicityKEGGhsa04650
Type I diabetes mellitusKEGGhsa04940
Alzheimer's diseaseKEGGhsa05010
Pathways in cancerKEGGhsa05200
Autoimmune thyroid diseaseKEGGhsa05320
Allograft rejectionKEGGhsa05330
Graft-versus-host diseaseKEGGhsa05332
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
African trypanosomiasisKEGGko05143
African trypanosomiasisKEGGhsa05143
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Hepatitis BKEGGhsa05161
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
FasL/ CD95L signalingREACTOMER-HSA-75157
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Programmed Cell DeathREACTOMER-HSA-5357801
Caspase activation via extrinsic apoptotic signalling pathwayREACTOMER-HSA-5357769
Ligand-dependent caspase activationREACTOMER-HSA-140534
Dimerization of procaspase-8REACTOMER-HSA-69416
Regulation by c-FLIPREACTOMER-HSA-3371378
Regulated NecrosisREACTOMER-HSA-5218859
RIPK1-mediated regulated necrosisREACTOMER-HSA-5213460
Regulation of necroptotic cell deathREACTOMER-HSA-5675482
CASP8 activity is inhibitedREACTOMER-HSA-5218900
TP53 Regulates Transcription of Cell Death GenesREACTOMER-HSA-5633008
TP53 Regulates Transcription of Death Receptors and LigandsREACTOMER-HSA-6803211
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
214307812011FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR.161
247932392014Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors.161
205057302010CD95 promotes tumour growth.134
191183842009The Fas-FADD death domain complex structure unravels signalling by receptor clustering.113
183284272008Yes and PI3K bind CD95 to signal invasion of glioblastoma.110
209356342010The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations.101
124145252002Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome.98
185128122008Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95.90
187874112008Vorinostat and sorafenib increase ER stress, autophagy and apoptosis via ceramide-dependent CD95 and PERK activation.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85


Doriane Sanséau ; Patrick Legembre

FAS (Fas cell surface death receptor)

Atlas Genet Cytogenet Oncol Haematol. 2014-11-01

Online version: http://atlasgeneticsoncology.org/gene/207/fas-(fas-cell-surface-death-receptor)