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(The assertion that the name of the tumor necrosis factor protein Fas is an acronym for "first apoptosis signal" is incorrect. Importantly, this information doesn't appear in the source supporting this assertion.)
 
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{{Infobox gene}}
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Fas or 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 ''FAS'' [[gene]].<ref name="pmid1385299">{{cite journal |vauthors=Lichter P, Walczak H, Weitz S, Behrmann I, Krammer PH | title = The human APO-1 (APT) antigen maps to 10q23, a region that is syntenic with mouse chromosome 19 | journal = Genomics | volume = 14 | issue = 1 | pages = 179–80 |date=September 1992 | pmid = 1385299 | doi = 10.1016/S0888-7543(05)80302-7}}</ref><ref name="pmid1385309">{{cite journal |vauthors=Inazawa J, Itoh N, Abe T, Nagata S | title = Assignment of the human Fas antigen gene (Fas) to 10q24.1 | journal = Genomics | volume = 14 | issue = 3 | pages = 821–2 |date=November 1992 | pmid = 1385309 | doi = 10.1016/S0888-7543(05)80200-9}}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = yes
}}
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_FAS_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1ddf.
| PDB = {{PDB2|1ddf}}
| Name = Fas death domain (TNF receptor superfamily, member 6)
| HGNCid = 11920
| Symbol = FAS
| AltSymbols =; ALPS1A; APO-1; APT1; CD95; FAS1; FASTM; TNFRSF6
| OMIM = 134637
| ECnumber =
| Homologene = 27
| MGIid = 95484
| GeneAtlas_image1 = PBB_GE_FAS_204780_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_FAS_204781_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_FAS_215719_x_at_tn.png
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| DateOfBotUpdate = 18:33, 21 October 2007 (UTC)
| Function = {{GNF_GO|id=GO:0004888 |text = transmembrane receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0042802 |text = identical protein binding}}
| Component = {{GNF_GO|id=GO:0005625 |text = soluble fraction}} {{GNF_GO|id=GO:0005829 |text = cytosol}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006461 |text = protein complex assembly}} {{GNF_GO|id=GO:0006915 |text = apoptosis}} {{GNF_GO|id=GO:0006916 |text = anti-apoptosis}} {{GNF_GO|id=GO:0006917 |text = induction of apoptosis}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0042981 |text = regulation of apoptosis}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 355
    | Hs_Ensembl = ENSG00000026103
    | Hs_RefseqProtein = NP_000034
    | Hs_RefseqmRNA = NM_000043
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 90739206
    | Hs_GenLoc_end = 90765521
    | Hs_Uniprot = P25445
    | Mm_EntrezGene = 14102
    | Mm_Ensembl = ENSMUSG00000024778
    | Mm_RefseqmRNA = NM_007987
    | Mm_RefseqProtein = NP_032013
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 19
    | Mm_GenLoc_start = 34356663
    | Mm_GenLoc_end = 34393767
    | Mm_Uniprot = Q6GT31
  }}
}}
{{SI}}
{{CMG}}


==Overview==
The Fas receptor is a [[Tumor necrosis factor receptor|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.<ref>{{cite journal  | author=Wajant H |title=The Fas signaling pathway: more than a paradigm. |journal=Science |volume=296 |issue= 5573 |pages= 1635–6 |year= 2002 |pmid= 12040174 |doi= 10.1126/science.1071553 }}</ref> FasR is located on [[chromosome 10]] in humans and 19 in mice. Similar sequences related by evolution ([[orthologs]])<ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: FAS coding sequence | url = http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000026103_FAS.xml }}</ref> are found in most [[mammals]].
The '''Fas receptor''' (FasR) is the most intensely studied [[Tumor necrosis factor receptor|death receptor]]. Its aliases include CD95, Apo-1, and [[tumor necrosis factors|tumor necrosis factor]] receptor superfamily, member 6 (TNFRSf6). The gene is situated on [[chromosome 10]] in humans and 19 in mice.  


==Isoforms==
== Gene ==
Previous reports have identified as many as eight splice variants, which are translated into seven [[isoforms]] of the protein.


Many of these isoforms are rare [[haplotypes]] that are usually associated with a state of disease.  
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 nine protein encoding [[exon]]s.


Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 [[transmembrane protein]].
== Protein ==


==Function==
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]].<ref name="pmid16109372">{{cite journal |vauthors=Izquierdo JM, Majós N, Bonnal S, Martínez C, Castelo R, Guigó R, Bilbao D, Valcárcel J | title = Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition | journal = Mol. Cell | volume = 19 | issue = 4 | pages = 475–84 |date=August 2005 | pmid = 16109372 | doi = 10.1016/j.molcel.2005.06.015 }}</ref>
Fas forms the [[death inducing signalling complex]] (DISC) upon ligand binding. Membrane-anchored [[Fas ligand]] trimer on the surface of an adjacent cell causes trimerization of Fas receptor. 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 [[endosome|endosomal]] machinery. This allows the [[adaptor molecule]] [[FADD]] to bind the death domain of Fas through its own death domain.<ref>{{cite journal|author = Huang B, ''et al.''|title= NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain|year= 1996|journal= Nature|volume=384|pages=638-41|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8967952}}</ref>
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.


FADD also contains a [[death effector domain]] (DED) near its amino terminus,<ref>{{cite journal|author= Eberstadt M, ''et al.''|title= NMR structure and mutagenesis of the FADD (Mort1) death-effector domain|year=1998|journal=Nature|volume=391|pages=941-5|url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9582077}}</ref>which facilitates binding to the DED of FADD-like ICE (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.
== Function ==


==Role in apoptosis==
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.
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.  
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.<ref>{{cite journal|author = Wang|title= The Fas–FADD death domain complex structure reveals the basis of DISC assembly and disease mutations|year= 2010|journal= Nat Struct Mol Biol|volume=17|pages=1324–29|doi= 10.1038/nsmb.1920|pmid = 20935634|issue=11|display-authors=etal|pmc=2988912}}</ref>
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.


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.
Upon ensuing death domain (DD) aggregation, the receptor complex is internalized via the cellular [[endosome|endosomal]] machinery. This allows the [[Signal transducing adaptor protein|adaptor molecule]] [[FADD]] to bind the death domain of Fas through its own death domain.<ref>{{cite journal|author = Huang B|title= NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain|year= 1996|journal= Nature|volume=384|pages=638–41|doi= 10.1038/384638a0|pmid = 8967952|issue = 6610|display-authors=etal}}</ref>


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.  
FADD also contains a [[death effector domain]] (DED) near its amino terminus,<ref>{{cite journal|author= Eberstadt M|title= NMR structure and mutagenesis of the FADD (Mort1) death-effector domain|year=1998|journal=Nature|volume=392|pages=941–5|doi= 10.1038/31972|pmid= 9582077|issue= 6679|display-authors=etal}}</ref> 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.


However, evidence for [[crosstalk]] between the extrinsic and intrinsic pathways exists in the Fas signal cascade.  
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.<ref name="pmid20505730">{{cite journal |vauthors=Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME | title = CD95 promotes tumour growth | journal = Nature | volume = 465 | issue = 7297 | pages = 492–6 |date=May 2010 | pmid = 20505730 | pmc = 2879093 | doi = 10.1038/nature09075 }}</ref>
 
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,<ref name="urlTumorscape">{{cite web | url = http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf | title = Tumorscape | format = | work = | publisher = The Broad Institute }}</ref> 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.<ref name="pmid22669972">{{cite journal |vauthors=Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Liles G, Lee J, Liu K | title = NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression | journal = J Biol Chem | volume = 287| issue = 30| pages = 25530–40|date=June 2012 | pmid = 22669972 | doi = 10.1074/jbc.M112.356279 | pmc = 3408167}}</ref> Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.<ref name="pmid22461695">{{cite journal |vauthors=Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K | title = Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo | journal = J. Immunol. | volume = 188 | issue = 9 | pages = 4441–9 |date=May 2012 | pmid = 22461695 | doi = 10.4049/jimmunol.1103035 | pmc = 3398838 }}</ref>
 
== 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 (biology)|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 [[BH3 interacting domain death agonist|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 [[Bcl-2 homologous antagonist killer|Bak]] and [[Bax (biochemistry)|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 [[inhibitor of apoptosis|inhibitors of apoptosis]] proteins (IAPs).
In most cell types, caspase-8 catalyzes the cleavage of the pro-apoptotic BH3-only protein [[BH3 interacting domain death agonist|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 [[Bcl-2 homologous antagonist killer|Bak]] and [[Bax (biochemistry)|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 [[inhibitor of apoptosis|inhibitors of apoptosis]] proteins (IAPs).
[[Image:Signal transduction pathways.svg|300px|thumb|center|Overview of signal transduction pathways involved in [[apoptosis]].]]
== Interactions ==
Fas receptor has been shown to [[Protein-protein interaction|interact]] with:
* [[Caspase 8]],<ref name=pmid15659383/><ref name=pmid9325248/><ref name=pmid9208847/>
* [[Caspase 10]],<ref name="pmid9045686">{{cite journal |vauthors=Vincenz C, Dixit VM | title = 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 | journal = J. Biol. Chem. | volume = 272 | issue = 10 | pages = 6578–83 |date=March 1997 | pmid = 9045686 | doi = 10.1074/jbc.272.10.6578 }}</ref>
* [[CFLAR]],<ref name=pmid9325248/><ref name="pmid9208847">{{cite journal |vauthors=Shu HB, Halpin DR, Goeddel DV | title = Casper is a FADD- and caspase-related inducer of apoptosis | journal = Immunity | volume = 6 | issue = 6 | pages = 751–63 |date=June 1997 | pmid = 9208847 | doi = 10.1016/S1074-7613(00)80450-1 }}</ref>
* [[FADD]],<ref name="pmid15659383">{{cite journal |vauthors=Gajate C, Mollinedo F | title = Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy | journal = J. Biol. Chem. | volume = 280 | issue = 12 | pages = 11641–7 |date=March 2005 | pmid = 15659383 | doi = 10.1074/jbc.M411781200 }}</ref><ref name="pmid9325248">{{cite journal |vauthors=MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES | title = Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL | journal = J. Biol. Chem. | volume = 272 | issue = 41 | pages = 25417–20 |date=October 1997 | pmid = 9325248 | doi = 10.1074/jbc.272.41.25417 }}</ref><ref name="pmid9082980">{{cite journal |vauthors=Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM | title = The receptor for the cytotoxic ligand TRAIL | journal = Science | volume = 276 | issue = 5309 | pages = 111–3 |date=April 1997 | pmid = 9082980 | doi = 10.1126/science.276.5309.111 }}</ref><ref name="pmid8967952">{{cite journal |vauthors=Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW | title = NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain | journal = Nature | volume = 384 | issue = 6610 | pages = 638–41 | year = 1996 | pmid = 8967952 | doi = 10.1038/384638a0 }}</ref><ref name="pmid7538907">{{cite journal |vauthors=Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM | title = FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis | journal = Cell | volume = 81 | issue = 4 | pages = 505–12 |date=May 1995 | pmid = 7538907 | doi = 10.1016/0092-8674(95)90071-3 }}</ref><ref name="pmid12107169">{{cite journal |vauthors=Thomas LR, Stillman DJ, Thorburn A | title = Regulation of Fas-associated death domain interactions by the death effector domain identified by a modified reverse two-hybrid screen | journal = J. Biol. Chem. | volume = 277 | issue = 37 | pages = 34343–8 |date=September 2002 | pmid = 12107169 | doi = 10.1074/jbc.M204169200 }}</ref>
* [[Fas ligand]],<ref name=pmid15659383/><ref name="pmid12887920">{{cite journal |vauthors=Micheau O, Tschopp J | title = Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes | journal = Cell | volume = 114 | issue = 2 | pages = 181–90 |date=July 2003 | pmid = 12887920 | doi = 10.1016/S0092-8674(03)00521-X }}</ref><ref name="pmid9126929">{{cite journal |vauthors=Starling GC, Bajorath J, Emswiler J, Ledbetter JA, Aruffo A, Kiener PA | title = Identification of amino acid residues important for ligand binding to Fas | journal = J. Exp. Med. | volume = 185 | issue = 8 | pages = 1487–92 |date=April 1997 | pmid = 9126929 | pmc = 2196280 | doi = 10.1084/jem.185.8.1487 }}</ref><ref name="pmid9228058">{{cite journal |vauthors=Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A, Peitsch MC, Tschopp J | title = Characterization of Fas (Apo-1, CD95)-Fas ligand interaction | journal = J. Biol. Chem. | volume = 272 | issue = 30 | pages = 18827–33 |date=July 1997 | pmid = 9228058 | doi = 10.1074/jbc.272.30.18827 }}</ref>
* [[PDCD6]],<ref name="pmid11606059">{{cite journal |vauthors=Jung YS, Kim KS, Kim KD, Lim JS, Kim JW, Kim E | title = Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells | journal = Biochem. Biophys. Res. Commun. | volume = 288 | issue = 2 | pages = 420–6 |date=October 2001 | pmid = 11606059 | doi = 10.1006/bbrc.2001.5769 }}</ref> and
* [[Small ubiquitin-related modifier 1]].<ref name="pmid8906799">{{cite journal |vauthors=Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET | title = Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin | journal = J. Immunol. | volume = 157 | issue = 10 | pages = 4277–81 |date=November 1996 | pmid = 8906799 | doi = }}</ref><ref name="pmid11112409">{{cite journal |vauthors=Ryu SW, Chae SK, Kim E | title = Interaction of Daxx, a Fas binding protein, with sentrin and Ubc9 | journal = Biochem. Biophys. Res. Commun. | volume = 279 | issue = 1 | pages = 6–10 |date=December 2000 | pmid = 11112409 | doi = 10.1006/bbrc.2000.3882 }}</ref>


==References==
==References==
{{reflist}}
{{Reflist|2}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|2}}
{{PBB_Further_reading
*{{cite journal  | author=Nagata S |title=Apoptosis by death factor. |journal=Cell |volume=88 |issue= 3 |pages= 355–65 |year= 1997 |pmid= 9039262 |doi=10.1016/S0092-8674(00)81874-7 }}
| citations =
*{{cite journal  |vauthors=Cascino I, Papoff G, Eramo A, Ruberti G |title=Soluble Fas/Apo-1 splicing variants and apoptosis. |journal=Front. Biosci. |volume=1 |issue=  |pages= d12–8 |year= 2004 |pmid= 9159204 |doi= 10.2741/A112 }}
*{{cite journal  | author=Nagata S |title=Apoptosis by death factor. |journal=Cell |volume=88 |issue= 3 |pages= 355-65 |year= 1997 |pmid= 9039262 |doi=  }}
*{{cite journal  | author=Uckun FM |title=Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. |journal=Biochem. Pharmacol. |volume=56 |issue= 6 |pages= 683–91 |year= 1998 |pmid= 9751072 |doi=10.1016/S0006-2952(98)00122-1 }}
*{{cite journal  | author=Cascino I, Papoff G, Eramo A, Ruberti G |title=Soluble Fas/Apo-1 splicing variants and apoptosis. |journal=Front. Biosci. |volume=1 |issue=  |pages= d12-8 |year= 2004 |pmid= 9159204 |doi= }}
*{{cite journal  | author=Krammer PH |title=CD95's deadly mission in the immune system. |journal=Nature |volume=407 |issue= 6805 |pages= 789–95 |year= 2000 |pmid= 11048730 |doi= 10.1038/35037728 }}
*{{cite journal  | author=Uckun FM |title=Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. |journal=Biochem. Pharmacol. |volume=56 |issue= 6 |pages= 683-91 |year= 1998 |pmid= 9751072 |doi=  }}
*{{cite journal  |vauthors=Siegel RM, Chan FK, Chun HJ, Lenardo MJ |title=The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. |journal=Nat. Immunol. |volume=1 |issue= 6 |pages= 469–74 |year= 2001 |pmid= 11101867 |doi= 10.1038/82712 }}
*{{cite journal  | author=Krammer PH |title=CD95's deadly mission in the immune system. |journal=Nature |volume=407 |issue= 6805 |pages= 789-95 |year= 2000 |pmid= 11048730 |doi= 10.1038/35037728 }}
*{{cite journal  | author=Yonehara S |title=Death receptor Fas and autoimmune disease: from the original generation to therapeutic application of agonistic anti-Fas monoclonal antibody. |journal=Cytokine Growth Factor Rev. |volume=13 |issue= 4–5 |pages= 393–402 |year= 2003 |pmid= 12220552 |doi=10.1016/S1359-6101(02)00024-2 }}
*{{cite journal  | author=Siegel RM, Chan FK, Chun HJ, Lenardo MJ |title=The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity. |journal=Nat. Immunol. |volume=1 |issue= 6 |pages= 469-74 |year= 2001 |pmid= 11101867 |doi= 10.1038/82712 }}
*{{cite journal  |vauthors=Choi C, Benveniste EN |title=Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. |journal=Brain Res. Brain Res. Rev. |volume=44 |issue= 1 |pages= 65–81 |year= 2004 |pmid= 14739003 |doi=10.1016/j.brainresrev.2003.08.007 }}
*{{cite journal  | author=Wajant H |title=The Fas signaling pathway: more than a paradigm. |journal=Science |volume=296 |issue= 5573 |pages= 1635-6 |year= 2002 |pmid= 12040174 |doi= 10.1126/science.1071553 }}
*{{cite journal  |vauthors=Poppema S, Maggio E, van den Berg A |title=Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. |journal=Leuk. Lymphoma |volume=45 |issue= 3 |pages= 423–31 |year= 2004 |pmid= 15160902 |doi=10.1080/10428190310001593166 }}
*{{cite journal  | author=Yonehara S |title=Death receptor Fas and autoimmune disease: from the original generation to therapeutic application of agonistic anti-Fas monoclonal antibody. |journal=Cytokine Growth Factor Rev. |volume=13 |issue= 4-5 |pages= 393-402 |year= 2003 |pmid= 12220552 |doi=  }}
*{{cite journal  | author=Choi C, Benveniste EN |title=Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. |journal=Brain Res. Brain Res. Rev. |volume=44 |issue= 1 |pages= 65-81 |year= 2004 |pmid= 14739003 |doi=  }}
*{{cite journal  | author=Poppema S, Maggio E, van den Berg A |title=Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations. |journal=Leuk. Lymphoma |volume=45 |issue= 3 |pages= 423-31 |year= 2004 |pmid= 15160902 |doi=  }}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* {{MeshName|fas+Receptor}}
* {{MeshName|FAS+Receptor}}


{{PDB Gallery|geneid=355}}
{{Clusters of differentiation}}
{{Clusters of differentiation}}
{{Tumor necrosis factor receptor superfamily}}
{{Tumor necrosis factor receptor superfamily}}
{{Fas apoptosis signaling pathway}}
{{Cytokine receptor modulators}}
{{DEFAULTSORT:Fas Receptor}}
[[Category:Immune system]]
[[Category:Immune system]]
[[Category:Programmed cell death]]
[[Category:Programmed cell death]]
[[Category:Signal transduction]]
[[Category:Signal transduction]]
{{WikiDoc Sources}}

Latest revision as of 17:14, 21 August 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez
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RefSeq (mRNA)

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RefSeq (protein)

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Fas or 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 FAS 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 nine 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 RNA binding 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).

File:Signal transduction pathways.svg
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 (September 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.
  2. Inazawa J, Itoh N, Abe T, Nagata S (November 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.
  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 (August 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.
  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 (11): 1324–29. doi:10.1038/nsmb.1920. PMC 2988912. PMID 20935634.
  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.
  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.
  9. Chen L, Park SM, Tumanov AV, Hau A, Sawada K, Feig C, Turner JR, Fu YX, Romero IL, Lengyel E, Peter ME (May 2010). "CD95 promotes tumour growth". Nature. 465 (7297): 492–6. doi:10.1038/nature09075. PMC 2879093. PMID 20505730.
  10. "Tumorscape". The Broad Institute.
  11. Liu F, Bardhan K, Yang D, Thangaraju M, Ganapathy V, Liles G, Lee J, Liu K (June 2012). "NF-κB directly regulates Fas transcription to modulate Fas-mediated apoptosis and tumor suppression". J Biol Chem. 287 (30): 25530–40. doi:10.1074/jbc.M112.356279. PMC 3408167. PMID 22669972.
  12. Yang D, Torres CM, Bardhan K, Zimmerman M, McGaha TL, Liu K (May 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. PMC 3398838. PMID 22461695.
  13. 13.0 13.1 13.2 Gajate C, Mollinedo F (March 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.
  14. 14.0 14.1 14.2 MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES (October 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.
  15. 15.0 15.1 Shu HB, Halpin DR, Goeddel DV (June 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.
  16. Vincenz C, Dixit VM (March 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.
  17. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM (April 1997). "The receptor for the cytotoxic ligand TRAIL". Science. 276 (5309): 111–3. doi:10.1126/science.276.5309.111. PMID 9082980.
  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.
  19. Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM (May 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.
  20. Thomas LR, Stillman DJ, Thorburn A (September 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.
  21. Micheau O, Tschopp J (July 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.
  22. Starling GC, Bajorath J, Emswiler J, Ledbetter JA, Aruffo A, Kiener PA (April 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.
  23. Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A, Peitsch MC, Tschopp J (July 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.
  24. Jung YS, Kim KS, Kim KD, Lim JS, Kim JW, Kim E (October 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.
  25. Okura T, Gong L, Kamitani T, Wada T, Okura I, Wei CF, Chang HM, Yeh ET (November 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.
  26. Ryu SW, Chae SK, Kim E (December 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.

Further reading

External links