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Revision as of 11:35, 5 September 2011


Fas death domain (TNF receptor superfamily, member 6)
PDB rendering based on 1ddf.
Available structures
PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB
Identifiers
Symbols FAS ; ALPS1A; APO-1; APT1; CD95; FAS1; FASTM; TNFRSF6
External IDs Template:OMIM5 Template:MGI HomoloGene27
RNA expression pattern
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a

WikiDoc Resources for Fas receptor

Articles

Most recent articles on Fas receptor

Most cited articles on Fas receptor

Review articles on Fas receptor

Articles on Fas receptor in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Fas receptor

Images of Fas receptor

Photos of Fas receptor

Podcasts & MP3s on Fas receptor

Videos on Fas receptor

Evidence Based Medicine

Cochrane Collaboration on Fas receptor

Bandolier on Fas receptor

TRIP on Fas receptor

Clinical Trials

Ongoing Trials on Fas receptor at Clinical Trials.gov

Trial results on Fas receptor

Clinical Trials on Fas receptor at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Fas receptor

NICE Guidance on Fas receptor

NHS PRODIGY Guidance

FDA on Fas receptor

CDC on Fas receptor

Books

Books on Fas receptor

News

Fas receptor in the news

Be alerted to news on Fas receptor

News trends on Fas receptor

Commentary

Blogs on Fas receptor

Definitions

Definitions of Fas receptor

Patient Resources / Community

Patient resources on Fas receptor

Discussion groups on Fas receptor

Patient Handouts on Fas receptor

Directions to Hospitals Treating Fas receptor

Risk calculators and risk factors for Fas receptor

Healthcare Provider Resources

Symptoms of Fas receptor

Causes & Risk Factors for Fas receptor

Diagnostic studies for Fas receptor

Treatment of Fas receptor

Continuing Medical Education (CME)

CME Programs on Fas receptor

International

Fas receptor en Espanol

Fas receptor en Francais

Business

Fas receptor in the Marketplace

Patents on Fas receptor

Experimental / Informatics

List of terms related to Fas receptor

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The Fas receptor (FasR) is the most intensely studied death receptor. Its aliases include CD95, Apo-1, and tumor necrosis factor receptor superfamily, member 6 (TNFRSf6). The gene is situated on chromosome 10 in humans and 19 in mice.

Isoforms

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.

Apoptosis-inducing Fas receptor is dubbed isoform 1 and is a type 1 transmembrane protein.

Function

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 endosomal machinery. This allows the adaptor molecule FADD to bind the death domain of Fas through its own death domain.[1]

FADD also contains a death effector domain (DED) near its amino terminus,[2]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.

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).

References

  1. Huang B; et al. (1996). "NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain". Nature. 384: 638–41.
  2. Eberstadt M; et al. (1998). "NMR structure and mutagenesis of the FADD (Mort1) death-effector domain". Nature. 391: 941–5.

Further reading

  • Nagata S (1997). "Apoptosis by death factor". Cell. 88 (3): 355–65. PMID 9039262.
  • Cascino I, Papoff G, Eramo A, Ruberti G (2004). "Soluble Fas/Apo-1 splicing variants and apoptosis". Front. Biosci. 1: d12–8. PMID 9159204.
  • Uckun FM (1998). "Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis". Biochem. Pharmacol. 56 (6): 683–91. PMID 9751072.
  • Krammer PH (2000). "CD95's deadly mission in the immune system". Nature. 407 (6805): 789–95. doi:10.1038/35037728. PMID 11048730.
  • Siegel RM, Chan FK, Chun HJ, Lenardo MJ (2001). "The multifaceted role of Fas signaling in immune cell homeostasis and autoimmunity". Nat. Immunol. 1 (6): 469–74. doi:10.1038/82712. PMID 11101867.
  • Wajant H (2002). "The Fas signaling pathway: more than a paradigm". Science. 296 (5573): 1635–6. doi:10.1126/science.1071553. PMID 12040174.
  • Yonehara S (2003). "Death receptor Fas and autoimmune disease: from the original generation to therapeutic application of agonistic anti-Fas monoclonal antibody". Cytokine Growth Factor Rev. 13 (4–5): 393–402. PMID 12220552.
  • Choi C, Benveniste EN (2004). "Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses". Brain Res. Brain Res. Rev. 44 (1): 65–81. PMID 14739003.
  • Poppema S, Maggio E, van den Berg A (2004). "Development of lymphoma in Autoimmune Lymphoproliferative Syndrome (ALPS) and its relationship to Fas gene mutations". Leuk. Lymphoma. 45 (3): 423–31. PMID 15160902.

External links

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