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FAS (Fas cell surface death receptor)

Written2014-11Doriane Sanséau, Patrick Legembre
Universite de Rennes-1, 2 Av. du Professeur Leon Bernard, 35043 Rennes, France, Centre Eugene Marquis, rue Bataille Flandres Dunkerque, 35042 Rennes, France, INSERM U1085, Equipe Labellisee Ligue Contre Le Cancer Death Receptors, Tumor Escape, 2 Avenue du Professeur Leon Bernard, 35043 Rennes, France

Abstract 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).

Keywords CD95, Fas, apoptosis, inflammation, auto-immunity, metastasis

(Note : for Links provided by Atlas : click)


HGNC Alias symbCD95
HGNC Alias nameTNF receptor superfamily member 6
HGNC Previous nameFAS1
HGNC Previous nametumor necrosis factor receptor superfamily, member 6
 Fas (TNF receptor superfamily, member 6)
LocusID (NCBI) 355
Atlas_Id 207
Location 10q23.31  [Link to chromosome band 10q23]
Location_base_pair Starts at 88990798 and ends at 89017059 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping FAS.png]
  Gene localisation: CD95 gene spans approximately 25 kb on human chromosome 10.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
FAS (10q23.31)::CTNND2 (5p15.2)PPM1B (2p21)::FAS (10q23.31)
Note Based on published GeneBank sequences, this gene has seven potential transcription start sites located at 88 969 796, 88 990 531, 88 990 657 and 90 750 288 bp from pter.


Note Gene annotation is APT1.
  According to Ensembl, CD95 gene is composed of 9 exons encoding 3 variants.
Description CD95 gene is composed of 9 exons.
Transcription 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.
Pseudogene No known pseudogenes.


Note Type I transmembrane protein.
  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.
Description 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).
  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).
Expression CD95 is ubiquitously expressed in human body.
Localisation 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).
Function 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.
Homology 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.


Note 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.
Germinal CD95 germinal mutations have been reported in ALPS type Ia.
Somatic CD95 somatic mutations have been reported in several cancers.

Implicated in

Entity Hodgkin's lymphoma
Note Hodgkin's lymphoma is a cancer of the immune system characterised by the presence of mononucleated Hodgkin's 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 hodgkin's 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).
Table1. Germinal mutations in the APT1 gene.
Oncogenesis 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 Various cancers
Note 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 Autoimmune lymphoproliferative syndrome type Ia
Note 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 Systemic lupus erythematous
Note 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.


Note No translocation within the APT-1 gene have been identified.


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Seeberger H, Starostik P, Schwarz S, Knorr C, Kalla J, Ott G, Muller-Hermelink HK, Greiner A.
Lab Invest. 2001 Jul;81(7):977-86.
PMID 11454987
Modulation of the CD95-induced apoptosis: the role of CD95 N-glycosylation.
Shatnyeva OM, Kubarenko AV, Weber CE, Pappa A, Schwartz-Albiez R, Weber AN, Krammer PH, Lavrik IN.
PLoS One. 2011;6(5):e19927. doi: 10.1371/journal.pone.0019927. Epub 2011 May 18.
PMID 21625644
Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer.
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.
Oncogene. 2002 Jun 13;21(26):4129-36.
PMID 12037669
Alterations of Fas (Apo-1/CD95) gene in cutaneous malignant melanoma.
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.
Am J Pathol. 1999 Jun;154(6):1785-91.
PMID 10362803
Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.
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Science. 2000 Jun 30;288(5475):2354-7.
PMID 10875918
How CD95 stimulates invasion.
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PMID 22064519
The many roles of FAS receptor signaling in the immune system.
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Immunity. 2009 Feb 20;30(2):180-92. doi: 10.1016/j.immuni.2009.01.001. (REVIEW)
PMID 19239902
The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis.
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.
Blood. 2001 Jul 1;98(1):194-200.
PMID 11418480
Frequent mutations of Fas gene in nasal NK/T cell lymphoma.
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Oncogene. 2002 Jul 11;21(30):4702-5.
PMID 12096347
Frequent Fas gene mutations in testicular germ cell tumors.
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PMID 12163388
The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway.
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The molecular interaction of Fas and FAP-1. A tripeptide blocker of human Fas interaction with FAP-1 promotes Fas-induced apoptosis.
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Blood. 2002 Feb 15;99(4):1492-4.
PMID 11830507


This paper should be referenced as such :
Doriane Sansau, Patrick Legembre
FAS (Fas cell surface death receptor)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(11):643-649.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 4 ]
  Classical Hodgkin lymphoma
Hodgkin lymphoma
Monomorphic PTLD (B- and T::NK-cell types)
Primary Cutaneous B-Cell Lymphomas

Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Autoimmune lymphoproliferative syndrome

External links

HGNC (Hugo)FAS   11920
LRG (Locus Reference Genomic)LRG_134
Entrez_Gene (NCBI)FAS    Fas cell surface death receptor
AliasesALPS1A; APO-1; APT1; CD95; 
GeneCards (Weizmann)FAS
Ensembl hg19 (Hinxton)ENSG00000026103 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000026103 [Gene_View]  ENSG00000026103 [Sequence]  chr10:88990798-89017059 [Contig_View]  FAS [Vega]
ICGC DataPortalENSG00000026103
TCGA cBioPortalFAS
Genatlas (Paris)FAS
SOURCE (Princeton)FAS
Genetics Home Reference (NIH)FAS
Genomic and cartography
GoldenPath hg38 (UCSC)FAS  -     chr10:88990798-89017059 +  10q23.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FAS  -     10q23.31   [Description]    (hg19-Feb_2009)
GoldenPathFAS - 10q23.31 [CytoView hg19]  FAS - 10q23.31 [CytoView hg38]
Genome Data Viewer NCBIFAS [Mapview hg19]  
OMIM134637   601859   
Gene and transcription
Genbank (Entrez)AB209361 AK026195 AK290978 AK311164 AK311424
RefSeq transcript (Entrez)NM_000043 NM_001320619 NM_152871 NM_152872 NM_152873 NM_152874 NM_152875 NM_152876 NM_152877
Consensus coding sequences : CCDS (NCBI)FAS
Gene ExpressionFAS [ NCBI-GEO ]   FAS [ EBI - ARRAY_EXPRESS ]   FAS [ SEEK ]   FAS [ MEM ]
Gene Expression Viewer (FireBrowse)FAS [ Firebrowse - Broad ]
GenevisibleExpression of FAS in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)355
GTEX Portal (Tissue expression)FAS
Human Protein AtlasENSG00000026103-FAS [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)FAS
Human Protein Atlas [tissue]ENSG00000026103-FAS [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:17:48 CEST 2021

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