Fas receptor

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Boghog (talk | contribs) at 19:04, 7 May 2013 (→‎External links: caps). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Template:PBB The FAS receptor (FasR), also known as 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 TNFRSF6 gene.[1][2]

The Fas receptor is a death receptor on the surface of cells that leads to programmed cell death (apoptosis). It is one of two apoptosis pathways, the other being the mitochondrial pathway.[3] FasR is located on chromosome 10 in humans and 19 in mice. Similar sequences related by evolution (orthologs)[4] are found in most mammals.

Gene

FAS receptor 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 organised into 9 protein encoding exons.

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 protein TIA1.[5]

The mature Fas protein has 319 amino acids, has a predicted molecular weight of 48 kiloDaltons and is divided into 3 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 extracelluar 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.[6] 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.[7]

FADD also contains a death effector domain (DED) near its amino terminus,[8] 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.[9]

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,[10] 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.[11] Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.[12]

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).

Overview of signal transduction pathways involved in apoptosis.

Interactions

Fas receptor has been shown to interact with:

References

  1. ^ Lichter P, Walczak H, Weitz S, Behrmann I, Krammer PH (1992). "The human APO-1 (APT) antigen maps to 10q23, a region that is syntenic with mouse chromosome 19". Genomics. 14 (1): 179–80. doi:10.1016/S0888-7543(05)80302-7. PMID 1385299. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Inazawa J, Itoh N, Abe T, Nagata S (1992). "Assignment of the human Fas antigen gene (Fas) to 10q24.1". Genomics. 14 (3): 821–2. doi:10.1016/S0888-7543(05)80200-9. PMID 1385309. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Wajant H (2002). "The Fas signaling pathway: more than a paradigm". Science. 296 (5573): 1635–6. doi:10.1126/science.1071553. PMID 12040174.
  4. ^ "OrthoMaM phylogenetic marker: FAS coding sequence".
  5. ^ Izquierdo JM, Majós N, Bonnal S, Martínez C, Castelo R, Guigó R, Bilbao D, Valcárcel J (2005). "Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition". Mol. Cell. 19 (4): 475–84. doi:10.1016/j.molcel.2005.06.015. PMID 16109372. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Wang; et al. (2010). "The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations". Nat Struct Mol Biol. 17: 1324–29. doi:10.1038/nsmb.1920. PMID 20935634. {{cite journal}}: Explicit use of et al. in: |author= (help)
  7. ^ Huang B; et al. (1996). "NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain". Nature. 384 (6610): 638–41. doi:10.1038/384638a0. PMID 8967952. {{cite journal}}: Explicit use of et al. in: |author= (help)
  8. ^ Eberstadt M; et al. (1998). "NMR structure and mutagenesis of the FADD (Mort1) death-effector domain". Nature. 392 (6679): 941–5. doi:10.1038/31972. PMID 9582077. {{cite journal}}: Explicit use of et al. in: |author= (help)
  9. ^ Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME (2010). "CD95 promotes tumour growth". Nature. 465 (7297): 492–6. doi:10.1038/nature09075. PMC 2879093. PMID 20505730. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ "Tumorscape". The Broad Institute.
  11. ^ Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Liles G, Lee J, Liu K (2012). "NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression". J Biol Chem. doi:10.1074/jbc.M112.356279. PMID 22669972. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  12. ^ Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K (2012). "Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo". J. Immunol. 188 (9): 4441–9. doi:10.4049/jimmunol.1103035. PMID 22461695. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b c 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 (12): 11641–7. doi:10.1074/jbc.M411781200. PMID 15659383. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  14. ^ a b c MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES (1997). "Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL". J. Biol. Chem. 272 (41): 25417–20. doi:10.1074/jbc.272.41.25417. PMID 9325248. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  15. ^ a b Shu HB, Halpin DR, Goeddel DV (1997). "Casper is a FADD- and caspase-related inducer of apoptosis". Immunity. 6 (6): 751–63. doi:10.1016/S1074-7613(00)80450-1. PMID 9208847. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Vincenz C, Dixit VM (1997). "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". J. Biol. Chem. 272 (10): 6578–83. doi:10.1074/jbc.272.10.6578. PMID 9045686. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  17. ^ Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (1997). "The receptor for the cytotoxic ligand TRAIL". Science. 276 (5309): 111–3. doi:10.1126/science.276.5309.111. PMID 9082980. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ 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 (6610): 638–41. doi:10.1038/384638a0. PMID 8967952.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ 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 (4): 505–12. doi:10.1016/0092-8674(95)90071-3. PMID 7538907. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ Thomas LR, Stillman DJ, Thorburn A (2002). "Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen". J. Biol. Chem. 277 (37): 34343–8. doi:10.1074/jbc.M204169200. PMID 12107169. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  21. ^ Micheau O, Tschopp J (2003). "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes". Cell. 114 (2): 181–90. doi:10.1016/S0092-8674(03)00521-X. PMID 12887920. {{cite journal}}: Unknown parameter |month= ignored (help)
  22. ^ Starling GC, Bajorath J, Emswiler J, Ledbetter JA, Aruffo A, Kiener PA (1997). "Identification of amino acid residues important for ligand binding to Fas". J. Exp. Med. 185 (8): 1487–92. doi:10.1084/jem.185.8.1487. PMC 2196280. PMID 9126929. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A, Peitsch MC, Tschopp J (1997). "Characterization of Fas (Apo-1, CD95)-Fas ligand interaction". J. Biol. Chem. 272 (30): 18827–33. doi:10.1074/jbc.272.30.18827. PMID 9228058. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  24. ^ Jung YS, Kim KS, Kim KD, Lim JS, Kim JW, Kim E (2001). "Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells". Biochem. Biophys. Res. Commun. 288 (2): 420–6. doi:10.1006/bbrc.2001.5769. PMID 11606059. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  25. ^ Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET (1996). "Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin". J. Immunol. 157 (10): 4277–81. PMID 8906799. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  26. ^ Ryu SW, Chae SK, Kim E (2000). "Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9". Biochem. Biophys. Res. Commun. 279 (1): 6–10. doi:10.1006/bbrc.2000.3882. PMID 11112409. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Fas_receptor&oldid=554002973"