Fas receptor

FAS
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1DDF, 3EWT, 3EZQ, 3THM, 3TJE, 2NA7
Identifiers
Aliases	FAS, ALPS1A, APO-1, APT1, CD95, FAS1, FASTM, TNFRSF6, Fas cell surface death receptor
External IDs	MGI: 95484 HomoloGene: 27 GeneCards: FAS
Gene ontology Molecular function • kinase binding • protein binding • transmembrane signaling receptor activity • receptor activity • signal transducer activity • identical protein binding • tumor necrosis factor-activated receptor activity Cellular component • cytosol • CD95 death-inducing signaling complex • membrane • extracellular region • nucleus • cell surface • extracellular exosome • integral component of membrane • plasma membrane • integral component of plasma membrane • external side of plasma membrane • death-inducing signaling complex • membrane raft • neuron projection • cytoplasm Biological process • renal system process • activation-induced cell death of T cells • tumor necrosis factor-mediated signaling pathway • T cell homeostasis • positive regulation of extrinsic apoptotic signaling pathway in absence of ligand • cellular response to mechanical stimulus • circadian rhythm • apoptotic signaling pathway • positive regulation of extrinsic apoptotic signaling pathway • regulation of extrinsic apoptotic signaling pathway via death domain receptors • activation of cysteine-type endopeptidase activity involved in apoptotic process • apoptotic process • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway • spleen development • regulation of cysteine-type endopeptidase activity involved in apoptotic process • negative thymic T cell selection • regulation of lymphocyte differentiation • necroptotic signaling pathway • motor neuron apoptotic process • inflammatory response • regulation of myeloid cell differentiation • protein homooligomerization • response to toxic substance • B cell mediated immunity • positive regulation of MAPK cascade • neuron apoptotic process • positive regulation of protein homooligomerization • cellular response to lithium ion • positive regulation of lymphocyte apoptotic process • negative regulation of apoptotic process • immune response • gene expression • protein complex assembly • cellular response to hyperoxia • negative regulation of B cell activation • response to glucocorticoid • brain development • extrinsic apoptotic signaling pathway in absence of ligand • inflammatory cell apoptotic process • extrinsic apoptotic signaling pathway via death domain receptors • immunoglobulin production • signal transduction • hepatocyte apoptotic process • response to lipopolysaccharide • extrinsic apoptotic signaling pathway • regulation of apoptotic process • positive regulation of apoptotic process • regulation of cell proliferation • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	355	14102
Ensembl	ENSG00000026103	ENSMUSG00000024778
UniProt	P25445	P25446
RefSeq (mRNA)	NM_000043 NM_152871 NM_152872 NM_152873 NM_152874 NM_152875 NM_152876 NM_152877 NM_001320619	NM_001146708 NM_007987
RefSeq (protein)	NP_000034.1 NP_690610.1 NP_690611.1 NP_001307548.1	NP_032013.2
Location (UCSC)	Chr 10: 88.99 – 89.02 Mb	Chr 19: 34.29 – 34.33 Mb
PubMed search	[1]	[2]
Wikidata

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 FAS gene.^[3][4]

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.^[5] FasR is located on chromosome 10 in humans and 19 in mice. Similar sequences related by evolution (orthologs)^[6] 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.^[7]

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.^[8] 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.^[9]

FADD also contains a death effector domain (DED) near its amino terminus,^[10] 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.^[11]

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,^[12] 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.^[13] Furthermore, the Fas receptor also mediates tumor-specific cytotoxic T lymphocyte (CTL) anti-tumor cytotoxicity.^[14]

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:

• Caspase 8,^[15][16][17]
• Caspase 10,^[18]
• CFLAR,^[16][17]
• FADD,^{[15][16][19][20][21][22]}
• Fas ligand,^{[15][23][24][25]}
• PDCD6,^[26] and
• Small ubiquitin-related modifier 1.^[27][28]

References

Further reading

External links

• FAS Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery
1ddf: FAS DEATH DOMAIN, NMR, MINIMIZED AVERAGE STRUCTURE