Fas receptor explained

The Fas receptor, also known as Fas, FasR, apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily member 6 (TNFRSF6), is a protein that in humans is encoded by the FAS gene.[1] [2] Fas was first identified using a monoclonal antibody generated by immunizing mice with the FS-7 cell line. Thus, the name Fas is derived from FS-7-associated surface antigen.[3]

The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis) if it binds its ligand, Fas ligand (FasL). It is one of two apoptosis pathways, the other being the mitochondrial pathway.[4]

Gene

FAS receptor gene is located on the long arm of chromosome 10 (10q24.1) in humans and on chromosome 19 in mice. The gene lies on the plus (Watson strand) and is 25,255 bases in length organized into nine protein encoding exons. Similar sequences related by evolution (orthologs)[5] are found in most mammals.

Protein

Previous reports have identified as many as eight splice variants, which are translated into seven isoforms of the protein. Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein. Many of the other isoforms are rare haplotypes that are usually associated with a state of disease. However, two isoforms, the apoptosis-inducing membrane-bound form and the soluble form, are normal products whose production via alternative splicing is regulated by the cytotoxic RNA binding protein TIA1.[6]

The mature Fas protein has 319 amino acids, has a predicted molecular weight of 48 kilodaltons and is divided into three domains: an extracellular domain, a transmembrane domain, and a cytoplasmic domain. The extracellular domain has 157 amino acids and is rich in cysteine residues. The transmembrane and cytoplasmic domains have 17 and 145 amino acids respectively. Exons 1 through 5 encode the extracellular region. Exon 6 encodes the transmembrane region. Exons 7-9 encode the intracellular region.

Function

Fas forms the death-inducing signaling complex (DISC) upon ligand binding. Membrane-anchored Fas ligand trimer on the surface of an adjacent cell causes oligomerization of Fas.Recent studies which suggested the trimerization of Fas could not be validated. Other models suggested the oligomerization up to 5–7 Fas molecules in the DISC.[7] This event is also mimicked by binding of an agonistic Fas antibody, though some evidence suggests that the apoptotic signal induced by the antibody is unreliable in the study of Fas signaling. To this end, several clever ways of trimerizing the antibody for in vitro research have been employed.

Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular endosomal machinery. This allows the adaptor molecule FADD to bind the death domain of Fas through its own death domain.[8]

FADD also contains a death effector domain (DED) near its amino terminus,[9] which facilitates binding to the DED of FADD-like interleukin-1 beta-converting enzyme (FLICE), more commonly referred to as caspase-8. FLICE can then self-activate through proteolytic cleavage into p10 and p18 subunits, two each of which form the active heterotetramer enzyme. Active caspase-8 is then released from the DISC into the cytosol, where it cleaves other effector caspases, eventually leading to DNA degradation, membrane blebbing, and other hallmarks of apoptosis.

Recently, Fas has also been shown to promote tumor growth, since during tumor progression, it is frequently downregulated or cells are rendered apoptosis resistant. Cancer cells in general, regardless of their Fas apoptosis sensitivity, depend on constitutive activity of Fas. This is stimulated by cancer-produced Fas ligand for optimal growth.[10]

Although Fas has been shown to promote tumor growth in the above mouse models, analysis of the human cancer genomics database revealed that FAS is not significantly focally amplified across a dataset of 3131 tumors (FAS is not an oncogene), but is significantly focally deleted across the entire dataset of these 3131 tumors,[11] suggesting that FAS functions as a tumor suppressor in humans.

In cultured cells, FasL induces various types of cancer cell apoptosis through the Fas receptor. In AOM-DSS-induced colon carcinoma and MCA-induced sarcoma mouse models, it has been shown that Fas acts as a tumor suppressor.[12] Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.[13] In addition to the well-described on-target CTL anti-tumor cytotoxicity, Fas has been ascribed with a distinct function – the induction of bystander tumor cell death even amongst cognate antigen non-expressing (bystander) cells. CTL-mediated bystander killing was described by the Fleischer Lab in 1986[14] and later attributed to fas-mediated lysis in vitro by the Austin Research Institute, Cellular Cytotoxicity Laboratory.[15] More recently, fas-mediated bystander tumor cell killing was demonstrated in vivo by the Lymphoma Immunotherapy Program at Mount Sinai School of Medicine using T cells and CAR-T cells,[16] similar to additional in vitro work using bispecific antibodies performed at Amgen.[17]

Role in apoptosis

Some reports have suggested that the extrinsic Fas pathway is sufficient to induce complete apoptosis in certain cell types through DISC assembly and subsequent caspase-8 activation. These cells are dubbed Type 1 cells and are characterized by the inability of anti-apoptotic members of the Bcl-2 family (namely Bcl-2 and Bcl-xL) to protect from Fas-mediated apoptosis. Characterized Type 1 cells include H9, CH1, SKW6.4 and SW480, all of which are lymphocyte lineages except the latter, which is a colon adenocarcinoma lineage. However, evidence for crosstalk between the extrinsic and intrinsic pathways exists in the Fas signal cascade.

In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein Bid into its truncated form, tBid. BH-3 only members of the Bcl-2 family exclusively engage anti-apoptotic members of the family (Bcl-2, Bcl-xL), allowing Bak and Bax to translocate to the outer mitochondrial membrane, thus permeabilizing it and facilitating release of pro-apoptotic proteins such as cytochrome c and Smac/DIABLO, an antagonist of inhibitors of apoptosis proteins (IAPs).

Interactions

Fas receptor has been shown to interact with:

Further reading

Notes and References

  1. Lichter P, Walczak H, Weitz S, Behrmann I, Krammer PH . The human APO-1 (APT) antigen maps to 10q23, a region that is syntenic with mouse chromosome 19 . Genomics . 14 . 1 . 179–80 . September 1992 . 1385299 . 10.1016/S0888-7543(05)80302-7 .
  2. Inazawa J, Itoh N, Abe T, Nagata S . Assignment of the human Fas antigen gene (Fas) to 10q24.1 . Genomics . 14 . 3 . 821–2 . November 1992 . 1385309 . 10.1016/S0888-7543(05)80200-9 .
  3. Nagata S . Early work on the function of CD95, an interview with Shige Nagata . Cell Death and Differentiation . 11 . Suppl 1 . S23-7 . July 2004 . 15143352 . 10.1038/sj.cdd.4401453 . free .
  4. Wajant H . The Fas signaling pathway: more than a paradigm . Science . 296 . 5573 . 1635–6 . May 2002 . 12040174 . 10.1126/science.1071553 . 2002Sci...296.1635W . 29449108 .
  5. Web site: OrthoMaM phylogenetic marker: FAS coding sequence. dead. https://web.archive.org/web/20160303165841/http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000026103_FAS.xml. 2016-03-03. 2009-12-02.
  6. Izquierdo JM, Majós N, Bonnal S, Martínez C, Castelo R, Guigó R, Bilbao D, Valcárcel J . 6 . Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition . Molecular Cell . 19 . 4 . 475–84 . August 2005 . 16109372 . 10.1016/j.molcel.2005.06.015 . free .
  7. Wang L, Yang JK, Kabaleeswaran V, Rice AJ, Cruz AC, Park AY, Yin Q, Damko E, Jang SB, Raunser S, Robinson CV, Siegel RM, Walz T, Wu H . 6 . The Fas-FADD death domain complex structure reveals the basis of DISC assembly and disease mutations . Nature Structural & Molecular Biology . 17 . 11 . 1324–9 . November 2010 . 20935634 . 2988912 . 10.1038/nsmb.1920 .
  8. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW . NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain . Nature . 384 . 6610 . 638–41 . 1996 . 8967952 . 10.1038/384638a0 . 1996Natur.384..638H . 2492303 .
  9. Eberstadt M, Huang B, Chen Z, Meadows RP, Ng SC, Zheng L, Lenardo MJ, Fesik SW . 6 . NMR structure and mutagenesis of the FADD (Mort1) death-effector domain . Nature . 392 . 6679 . 941–5 . April 1998 . 9582077 . 10.1038/31972 . 1998Natur.392..941E . 4370202 .
  10. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME . 6 . CD95 promotes tumour growth . Nature . 465 . 7297 . 492–6 . May 2010 . 20505730 . 2879093 . 10.1038/nature09075 . 2010Natur.465..492C .
  11. Web site: Tumorscape . The Broad Institute . 2012-07-05 . https://web.archive.org/web/20120414021752/http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf . 2012-04-14 . dead .
  12. Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Waller JL, Liles GB, Lee JR, Liu K . 6 . NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression . The Journal of Biological Chemistry . 287 . 30 . 25530–40 . July 2012 . 22669972 . 3408167 . 10.1074/jbc.M112.356279 . free .
  13. Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K . Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo . Journal of Immunology . 188 . 9 . 4441–9 . May 2012 . 22461695 . 3398838 . 10.4049/jimmunol.1103035 .
  14. Fleischer B . Lysis of bystander target cells after triggering of human cytotoxic T lymphocytes . European Journal of Immunology . 16 . 8 . 1021–4 . August 1986 . 3488908 . 10.1002/eji.1830160826 . 27562316 .
  15. Smyth MJ, Krasovskis E, Johnstone RW . Fas ligand-mediated lysis of self bystander targets by human papillomavirus-specific CD8+ cytotoxic T lymphocytes . Journal of Virology . 72 . 7 . 5948–54 . July 1998 . 9621057 . 110399 . 10.1128/JVI.72.7.5948-5954.1998 .
  16. Upadhyay R, Boiarsky JA, Pantsulaia G, Svensson-Arvelund J, Lin MJ, Wroblewska A, Bhalla S, Scholler N, Bot A, Rossi JM, Sadek N, Parekh S, Baccarini A, Merad M, Brown BD, Brody JD . 6 . A critical role for fas-mediated off-target tumor killing in T cell immunotherapy . Cancer Discovery . December 2020 . 11 . 3 . 599–613 . 33334730 . 10.1158/2159-8290.CD-20-0756 . 2159-8274 . 7933082 . free .
  17. Ross SL, Sherman M, McElroy PL, Lofgren JA, Moody G, Baeuerle PA, Coxon A, Arvedson T . 6 . Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing . PLOS ONE . 12 . 8 . e0183390 . 2017-08-24 . 28837681 . 5570333 . 10.1371/journal.pone.0183390 . 2017PLoSO..1283390R . free .
  18. Vincenz C, Dixit VM . Fas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling . The Journal of Biological Chemistry . 272 . 10 . 6578–83 . March 1997 . 9045686 . 10.1074/jbc.272.10.6578 . free .
  19. Shu HB, Halpin DR, Goeddel DV . Casper is a FADD- and caspase-related inducer of apoptosis . Immunity . 6 . 6 . 751–63 . June 1997 . 9208847 . 10.1016/S1074-7613(00)80450-1 . free .
  20. Gajate C, Mollinedo F . Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy . The Journal of Biological Chemistry . 280 . 12 . 11641–7 . March 2005 . 15659383 . 10.1074/jbc.M411781200 . free .
  21. MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES . Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL . The Journal of Biological Chemistry . 272 . 41 . 25417–20 . October 1997 . 9325248 . 10.1074/jbc.272.41.25417 . free.
  22. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM . The receptor for the cytotoxic ligand TRAIL . Science . 276 . 5309 . 111–3 . April 1997 . 9082980 . 10.1126/science.276.5309.111 . 19984057 .
  23. Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW . NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain . Nature . 384 . 6610 . 638–41 . 1996 . 8967952 . 10.1038/384638a0 . 1996Natur.384..638H . 2492303 .
  24. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM . FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis . Cell . 81 . 4 . 505–12 . May 1995 . 7538907 . 10.1016/0092-8674(95)90071-3 . 16906755 . free .
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  30. Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET . 6 . Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin . Journal of Immunology . 157 . 10 . 4277–81 . November 1996 . 10.4049/jimmunol.157.10.4277 . 8906799 . 38606511 . free .
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