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CD95; Fas antigen; tumor necrosis factor receptor superfamily member 6; apo-1 antigen; apoptosis-mediating surface antigen FAS; FASLG receptor (FAS, APT1, FAS1, TNFRSF6)

Function: - mediates apoptosis - ligand for Fas is a transmembrane glycoprotein FasL - recruits caspase-8 to the activated receptor - the resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases mediating apoptosis - FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both - secreted isoforms 2-6 block apoptosis (in vitro) - Fas/FasL & perforin/granzyme systems account for cytotoxic T-cell induced apoptosis [9] - Ca+2-independent killing by cytotoxic T-cells is mediated via fas/Apo1 - genes for Fas & FasL may be considered tumor suppressor genes - under certain circumstances, Fas activation has been reported to stimulate lymphocyte proliferation rather than apoptosis [5] - Fas antigen-induced apoptosis is initiated by receptor clustering - downstream effectors of Fas antigen include members of the interleukin-1 beta converting enzyme (ICE) - binds DAXX - interacts with HIPK3 - part of a complex containing HIPK3 & FADD (putative) - binds RIPK1 & FAIM2 - interacts with BRE & FEM1B - interacts with FADD Structure: - N-glycosylated & O-glycosylated - O-glycosylated with core 1 or possibly core 8 glycans - member of the TNF receptor family - the FasL signal is transduced through the Fas antigen cytoplasmic 'death domain' - contains 1 death domain - contains 3 TNFR-Cys repeats Compartment: - isoform 1: - cell membrane, single-pass type 1 membrane protein - isoform 2: secreted - isoform 3: secreted - isoform 4: secreted - isoform 5: secreted - isoform 6: secreted - at least one isoform may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay Alternative splicing: named isoforms=6 Expression: - activated B cells - activated T cells - resting T cells (low levels) - breast - vaginal, endometrial & ovarian epithelium - isoform 1 & isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells - after activation there is an increase in isoform 1 & decrease in the levels of isoform 6 Pathology: 1) expressed in: a) thyroid epithelial cells in Hashimoto's thyroiditis b) Reed-Sternberg cells in classic Hodgkin's lymphoma c) Barrett's esophagus d) esophageal adenocarcinoma 2) loss of function mutation in the Fas/FasL system induces - autoimmune lymphoproliferative syndrome (ALPS) or Canale-Smith syndrome (CSS) [6,7]

Interactions

molecular events

Related

apoptosis CD4+CD95+ cells in blood CD8+CD95+ cells in blood Fas ligand; tumor necrosis factor ligand superfamily member 6; Fas antigen ligand; CD95L protein; apoptosis antigen ligand; APTL; CD178 (FASLG, APT1LG1, FASL, TNFSF6) fas/Apo-1 gene (CD95 gene, murine lpr gene) protein tyrosine phosphatase 13, non-receptor type; Fas-associated phosphatase-1; FAP-1, protein-tyrosine phosphatase 1E (PTPN13, PNP1, PTP1E, PTPL1)

Specific

fas delta tm

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen human longevity protein pro apoptotic protein tumor necrosis factor [TNF] receptor family

Properties

SIZE: entity length = 335 aa MW = 38 kD COMPARTMENT: plasma membrane MOTIF: signal sequence {1-25} TNFR-Cys {47-83} MOTIF: cysteine residue {C59} MODIFICATION: cysteine residue {C73} cysteine residue {C63} MODIFICATION: cysteine residue {C82} cysteine residue {C73} MODIFICATION: cysteine residue {C59} cysteine residue {C82} MODIFICATION: cysteine residue {C63} TNFR-Cys {84-127} MOTIF: cysteine residue {C85} MODIFICATION: cysteine residue {C101} cysteine residue {C101} MODIFICATION: cysteine residue {C85} cysteine residue {C104} MODIFICATION: cysteine residue {C119} cysteine residue {C107} MODIFICATION: cysteine residue {C127} N-glycosylation site {N118} cysteine residue {C119} MODIFICATION: cysteine residue {C104} cysteine residue {C127} MODIFICATION: cysteine residue {C107} TNFR-Cys {128-166} MOTIF: cysteine residue {C129} MODIFICATION: cysteine residue {C143} N-glycosylation site {N136} cysteine residue {C143} MODIFICATION: cysteine residue {C129} cysteine residue {C146} MODIFICATION: cysteine residue {C157} cysteine residue {C149} MODIFICATION: cysteine residue {C165} cysteine residue {C157} MODIFICATION: cysteine residue {C146} cysteine residue {C165} MODIFICATION: cysteine residue {C149} transmembrane domain {174-190} Ser phosphorylation site {S209} HIPK3 interaction {212-317} MOTIF: Thr phosphorylation site {T214} death domain NAME: death domain SITE: 230-314

References

  1. Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992 Mar 26;356(6367):314-7. PMID: 1372394
  2. Taga T & Kishimoto T Cytokine receptors and signal transduction FASEB J 6:3387 1992 PMID: 1334470
  3. Cory S. Apoptosis. Fascinating death factor. Nature. 1994 Jan 27;367(6461):317-8. PMID: 7509455
  4. Nagata S, Golstein P. The Fas death factor. Science. 1995 Mar 10;267(5203):1449-56. Review. PMID: 7533326
  5. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456-62. Review. PMID: 7878464
  6. Rieux-Laucat F, Le Deist F, Hivroz C, Roberts IA, Debatin KM, Fischer A, de Villartay JP. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995 Jun 2;268(5215):1347-9. PMID: 7539157
  7. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Lenardo MJ, Puck JM. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995 Jun 16;81(6):935-46. PMID: 7540117
  8. Lacronique V, Mignon A, Fabre M, Viollet B, Rouquet N, Molina T, Porteu A, Henrion A, Bouscary D, Varlet P, Joulin V, Kahn A. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med. 1996 Jan;2(1):80-6. PMID: 8564847
  9. Kagi D, Vignaux F, Ledermann B et al Fas and perforin pathways as major mechanisms of T cell- mediated cytotoxicity. Science. 1994 Jul 22;265(5171):528-30. PMID: 7518614
  10. http://www.pathologyoutlines.com/cdmarkers.html 11 June 2005

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 134637 UniProt P25445 PFAM correlations Entrez Gene 355 KEGG correlations Figures/diagrams/slides/tables related to Fas antigen