同: CD178

同: CD178

WordNet

a substance (an atom or molecule or radical or ion) that forms a complex around a central atom
the 6th letter of the Roman alphabet (同)f

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/06 00:22:28」(JST)

Fas ligand (FasL or CD95L) is a type-II transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis. Fas ligand/receptor interactions play an important role in the regulation of the immune system and the progression of cancer.

Structure

Fas ligand or FasL is a homotrimeric type II transmembrane protein expressed on cytotoxic T lymphocytes. It signals through trimerization of FasR, which spans the membrane of the "target" cell. This trimerization usually leads to apoptosis, or cell death.

Soluble Fas ligand is generated by cleaving membrane-bound FasL at a conserved cleavage site by the external matrix metalloproteinase MMP-7.

Receptors

FasR: The Fas receptor (FasR), or CD95, is the most intensely studied member of the death receptor family. The gene is situated on chromosome 10 in humans and 19 in mice. 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. It consists of three cysteine-rich pseudorepeats, a transmembrane domain, and an intracellular death domain.

DcR3: Decoy receptor 3 (DcR3) is a recently discovered decoy receptor of the tumor necrosis factor superfamily that binds to FasL, LIGHT, and TLA1. DcR3 is a soluble receptor that has no signal transduction capabilities (hence a "decoy") and functions to prevent FasR-FasL interactions by competitively binding to membrane-bound Fas ligand and rendering them inactive.^[1]

Cell signalling

Fas forms the death-inducing signaling 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 Fas-associated death domain (FADD) to bind the death domain of Fas through its own death domain. FADD also contains a death effector domain (DED) near its amino terminus, 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, of which two 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.

Signaling pathways of Fas. Dashed grey lines represent multiple steps in JNK signaling

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 of the colon adenocarcinoma lineage.

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 engage exclusively 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).

Soluble FasL is less active than its membrane-bound counterpart and does not induce receptor trimerization and DISC formation.

Functions

Overview of signal transduction pathways involved in apoptosis

Apoptosis triggered by Fas-Fas ligand binding plays a fundamental role in the regulation of the immune system. Its functions include:

T-cell homeostasis: the activation of T-cells leads to their expression of the Fas ligand. T cells are initially resistant to Fas-mediated apoptosis during clonal expansion, but become progressively more sensitive the longer they are activated, ultimately resulting in activation-induced cell death (AICD). This process is needed to prevent an excessive immune response and eliminate autoreactive T-cells. Humans and mice with deleterious mutations of Fas or Fas ligand develop an accumulation of aberrant T-cells, leading to lymphadenopathy, splenomegaly, and lupus erythematosus.
Cytotoxic T-cell activity: Fas-induced apoptosis and the perforin pathway are the two main mechanisms by which cytotoxic T lymphocytes induce cell death in cells expressing foreign antigens.^[2]
Immune privilege: Cells in immune privileged areas such as the cornea or testes express Fas ligand and induce the apoptosis of infiltrating lymphocytes. It is one of many mechanisms the body employs in the establishment and maintenance of immune privilege.
Maternal tolerance: Fas ligand may be instrumental in the prevention of leukocyte trafficking between the mother and the fetus, although no pregnancy defects have yet been attributed to a faulty Fas-Fas ligand system.
Tumor counterattack: Tumors may over-express Fas ligand and induce the apoptosis of infiltrating lymphocytes, allowing the tumor to escape the effects of an immune response.^[3] The up-regulation of Fas ligand often occurs following chemotherapy, from which the tumor cells have attained apoptosis resistance.

Role in disease

Defective Fas-mediated apoptosis may lead to oncogenesis as well as drug resistance in existing tumors. Germline mutation of Fas is associated with autoimmune lymphoproliferative syndrome (ALPS), a childhood disorder of apoptosis.

Interactions

Fas ligand has been shown to interact with:

CASP8,^[4]^[5]
EZR,^[4]^[6]
FADD,^[4]^[5]
FNBP1,^[7]
FYN,^[8]^[9]
FAS,^[4]^[5]^[10]^[11]
Grb2,^[7]^[8]
PACSIN2,^[7] and
TNFRSF6B.^[12]^[13]^[14]

References

^ Sheikh MS, Fornace AJ (2000). "Death and decoy receptors and p53-mediated apoptosis". Leukemia 14 (8): 1509–1513. doi:10.1038/sj.leu.2401865. PMID 10942251.
^ Andersen MH, Schrama D, Thor Straten P, Becker JC (2006). "Cytotoxic T cells". J. Invest. Dermatol. 126 (1): 32–41. doi:10.1038/sj.jid.5700001. PMID 16417215.
^ Igney FH, Krammer PH (2005). "Tumor counterattack: fact or fiction?". Cancer Immunol. Immunother. 54 (11): 1127–1136. doi:10.1007/s00262-005-0680-7. PMID 15889255.
^ ^a ^b ^c ^d 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.
^ ^a ^b ^c 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.
^ Parlato S, Giammarioli AM, Logozzi M, Lozupone F, Matarrese P, Luciani F et al. (October 2000). "CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway". EMBO J. 19 (19): 5123–34. doi:10.1093/emboj/19.19.5123. PMC 302100. PMID 11013215.
^ ^a ^b ^c Ghadimi MP, Sanzenbacher R, Thiede B, Wenzel J, Jing Q, Plomann M et al. (May 2002). "Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)". FEBS Lett. 519 (1-3): 50–8. doi:10.1016/s0014-5793(02)02709-6. PMID 12023017.
^ ^a ^b Wenzel J, Sanzenbacher R, Ghadimi M, Lewitzky M, Zhou Q, Kaplan DR et al. (December 2001). "Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor". FEBS Lett. 509 (2): 255–62. doi:10.1016/s0014-5793(01)03174-x. PMID 11741599.
^ Hane M, Lowin B, Peitsch M, Becker K, Tschopp J (October 1995). "Interaction of peptides derived from the Fas ligand with the Fyn-SH3 domain". FEBS Lett. 373 (3): 265–8. doi:10.1016/0014-5793(95)01051-f. PMID 7589480.
^ 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.
^ Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A et al. (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.
^ Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS (May 1999). "A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis". J. Biol. Chem. 274 (20): 13733–6. doi:10.1074/jbc.274.20.13733. PMID 10318773.
^ Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC et al. (May 2002). "Modulation of dendritic cell differentiation and maturation by decoy receptor 3". J. Immunol. 168 (10): 4846–53. doi:10.4049/jimmunol.168.10.4846. PMID 11994433.
^ Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P et al. (December 1998). "Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer". Nature 396 (6712): 699–703. doi:10.1038/25387. PMID 9872321.

External links

GeneReviews/NCBI/NIH/UW entry on Autoimmune Lymphoproliferative Syndrome
Online 'Mendelian Inheritance in Man' (OMIM) 601859
Fas Ligand Protein at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 自己免疫性リンパ増殖症候群(ALPS)：疫学および病因 autoimmune lymphoproliferative syndrome alps epidemiology and pathogenesis
2. 自己免疫性リンパ増殖症候群(ALPS)：臨床的特徴および診断 autoimmune lymphoproliferative syndrome alps clinical features and diagnosis
3. 自己免疫性リンパ増殖症候群(ALPS)：管理および予後 autoimmune lymphoproliferative syndrome alps management and prognosis
4. 急性腎同種移植片拒絶反応の診断における検査方法 investigational methods in the diagnosis of acute renal allograft rejection
5. 橋本病（慢性自己免疫性甲状腺炎）の病因 pathogenesis of hashimotos thyroiditis chronic autoimmune thyroiditis

English Journal

Ligand engagement on material surfaces is discriminated by cell mechanosensoring.

Battista E1, Causa F2, Lettera V3, Panzetta V1, Guarnieri D1, Fusco S1, Gentile F4, Netti PA5.
Biomaterials.Biomaterials.2015 Mar;45:72-80. doi: 10.1016/j.biomaterials.2014.12.012. Epub 2015 Jan 14.
Peptide or protein ligands can be used for molecular decoration to enhance the functionality of synthetic materials. However, some skepticism has arisen about the efficacy of such strategy in practical contexts since serum proteins largely adsorb. To address this issue, it is crucial to ascertain wh
PMID 25662497

c-CBL E3 Ubiquitin Ligase Is Overexpressed in Cutaneous T-Cell Lymphoma: Its Inhibition Promotes Activation-Induced Cell Death.

Wu J1, Salva KA1, Wood GS1.
The Journal of investigative dermatology.J Invest Dermatol.2015 Mar;135(3):861-8. doi: 10.1038/jid.2014.364. Epub 2014 Aug 14.
Mycosis fungoides and Sézary syndrome are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death, which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS
PMID 25140833

Baicalein induces apoptosis of human cervical cancer HeLa cells in vitro.

Peng Y1, Guo C1, Yang Y2, Li F3, Zhang Y1, Jiang B1, Li Q4.
Molecular medicine reports.Mol Med Rep.2015 Mar;11(3):2129-34. doi: 10.3892/mmr.2014.2885. Epub 2014 Nov 6.
A number of studies have shown that baicalein shows high antitumor activity in vitro and in vivo. In this study, the inhibitory effect of baicalein on human cervical cancer HeLa cells was studied in vitro. HeLa cells were treated with high (100 µg/ml) and low (50 µg/ml) doses of baicalein, and cel
PMID 25373554

Japanese Journal

Stevens-Johnson症候群および中毒性表皮壊死症の発症機序とアフェレシス(<特集>皮膚難病とアフェレシス)

阿部理一郎
日本アフェレシス学会雑誌 32(2), 121-123, 2013-05-31
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is considered part of a spectrum of adverse cutaneous drug reactions showing severe and extensive skin detachment. SJS/TEN is morphologi …
NAID 110009611597

Augmentation of RANKL-induced osteoclast differentiation by Z-VAD-fmk, a pan-caspase inhibitor

Katao Yuko,Sawai Hirofumi,Shishido Mika,Omae Aki,Liao Wen,Inami Kaoru,Matsumoto Naoyuki
Journal of Osaka Dental University 47(1), 41-46, 2013-04
… Several members of the TNF family including TNF and Fas ligand can induce apoptosis via activation of caspases (especially caspase-3) in various cells. …
NAID 110009603277

Type-I Interferon is Critical for FasL Expression on Lung Cells to Determine the Severity of Influenza

Fujikura Daisuke,Chiba Satoko,Muramatsu Daisuke,Kazumata Mika,Nakayama Yosuke,Kawai Taro,Akira Shizuo,Kida Hiroshi,Miyazaki Tadaaki
PLoS One 8(2), e55321, 2013-02-08
… FasL is a specific ligand of Fas, which is a type-I transmembrane protein to induce cell death. … Previously, it has been reported that the hyper induction of gene expression associated with Fas signal is observed in lethal influenza A virus infection. … However, regulation of the induction of FasL or Fas by influenza A virus infection is still unknown. …
NAID 120005228345

「FasL protein」

Fas ligand (TNF superfamily, member 6)
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1BZI, 4MSV
Identifiers
Symbols	FASLG ; ALPS1B; APT1LG1; APTL; CD178; CD95-L; CD95L; FASL; TNFSF6
External IDs	OMIM: 134638 MGI: 99255 HomoloGene: 533 ChEMBL: 5714 GeneCards: FASLG Gene
Gene ontology
Molecular function	• receptor binding; • cytokine activity; • tumor necrosis factor receptor binding; • protein binding;
Cellular component	• extracellular region; • extracellular space; • nucleus; • integral component of plasma membrane; • caveola; • external side of plasma membrane; • lysosomal lumen; • perinuclear region of cytoplasm; • cytoplasmic membrane-bounded vesicle lumen; • extracellular vesicular exosome;
Biological process	• negative regulation of transcription from RNA polymerase II promoter; • transcription, DNA-templated; • apoptotic process; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • inflammatory cell apoptotic process; • immune response; • signal transduction; • cell-cell signaling; • positive regulation of cell proliferation; • extrinsic apoptotic signaling pathway via death domain receptors; • negative regulation of angiogenesis; • cellular chloride ion homeostasis; • response to lipopolysaccharide; • positive regulation of apoptotic process; • positive regulation of I-kappaB kinase/NF-kappaB signaling; • positive regulation of neuron apoptotic process; • positive regulation of epidermal growth factor receptor signaling pathway; • retinal cell programmed cell death; • endosomal lumen acidification; • T cell apoptotic process; • necroptotic process; • response to growth factor; • apoptotic signaling pathway; • extrinsic apoptotic signaling pathway; • necroptotic signaling pathway; • positive regulation of endothelial cell apoptotic process; • regulation of extrinsic apoptotic signaling pathway in absence of ligand;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

Fasリガンドタンパク質、FasLタンパク質

関: CD95 ligand、CD95L、Fas ligand、Fas ligand protein

「CD95 ligand」

　　[★]

CD95リガンド

関: CD95L、Fas ligand、Fas ligand protein、FasL protein

「Fasリガンド」

　　[★]

英: Fas ligand、FasL
関: Fasリガンドタンパク質、CD95リガンド

「Fas protein」

　　[★]

Fasタンパク質

Fas ligand

「FasL」

　　[★]

Fasリガンド

関: Fas ligand

「Fas ligand protein」

　　[★]

Fasリガンドタンパク質

関: CD95 ligand、CD95L、Fas ligand、FasL protein

Fas ligand

「FAS」

　　[★]

胎児性アルコール症候群 fetal alcohol syndrome
脂肪酸合成酵素 fatty acid synthetase：fatty acid synthetase 1、fatty acid synthetase 2
(アポトーシスに関連)CD95 Fas

「F」

　　[★] フェニルアラニン phenylalanine 　

[1] Yonehara S, Ishii A, Yonehara M. "A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor". J. Exp. Med. 169 (5): 1747–1756.

[pmid10942251-1] Sheikh MS, Fornace AJ (2000). "Death and decoy receptors and p53-mediated apoptosis". Leukemia 14 (8): 1509–1513. doi:10.1038/sj.leu.2401865. PMID 10942251.

[pmid16417215-2] Andersen MH, Schrama D, Thor Straten P, Becker JC (2006). "Cytotoxic T cells". J. Invest. Dermatol. 126 (1): 32–41. doi:10.1038/sj.jid.5700001. PMID 16417215.

[pmid15889255-3] Igney FH, Krammer PH (2005). "Tumor counterattack: fact or fiction?". Cancer Immunol. Immunother. 54 (11): 1127–1136. doi:10.1007/s00262-005-0680-7. PMID 15889255.

[pmid15659383-4] 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.

[pmid12887920-5] 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.

[pmid11013215-6] Parlato S, Giammarioli AM, Logozzi M, Lozupone F, Matarrese P, Luciani F et al. (October 2000). "CD95 (APO-1/Fas) linkage to the actin cytoskeleton through ezrin in human T lymphocytes: a novel regulatory mechanism of the CD95 apoptotic pathway". EMBO J. 19 (19): 5123–34. doi:10.1093/emboj/19.19.5123. PMC 302100. PMID 11013215.

[pmid12023017-7] Ghadimi MP, Sanzenbacher R, Thiede B, Wenzel J, Jing Q, Plomann M et al. (May 2002). "Identification of interaction partners of the cytosolic polyproline region of CD95 ligand (CD178)". FEBS Lett. 519 (1-3): 50–8. doi:10.1016/s0014-5793(02)02709-6. PMID 12023017.

[pmid11741599-8] Wenzel J, Sanzenbacher R, Ghadimi M, Lewitzky M, Zhou Q, Kaplan DR et al. (December 2001). "Multiple interactions of the cytosolic polyproline region of the CD95 ligand: hints for the reverse signal transduction capacity of a death factor". FEBS Lett. 509 (2): 255–62. doi:10.1016/s0014-5793(01)03174-x. PMID 11741599.

[pmid7589480-9] Hane M, Lowin B, Peitsch M, Becker K, Tschopp J (October 1995). "Interaction of peptides derived from the Fas ligand with the Fyn-SH3 domain". FEBS Lett. 373 (3): 265–8. doi:10.1016/0014-5793(95)01051-f. PMID 7589480.

[pmid9126929-10] 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.

[pmid9228058-11] Schneider P, Bodmer JL, Holler N, Mattmann C, Scuderi P, Terskikh A et al. (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.

[pmid10318773-12] Yu KY, Kwon B, Ni J, Zhai Y, Ebner R, Kwon BS (May 1999). "A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis". J. Biol. Chem. 274 (20): 13733–6. doi:10.1074/jbc.274.20.13733. PMID 10318773.

[pmid11994433-13] Hsu TL, Chang YC, Chen SJ, Liu YJ, Chiu AW, Chio CC et al. (May 2002). "Modulation of dendritic cell differentiation and maturation by decoy receptor 3". J. Immunol. 168 (10): 4846–53. doi:10.4049/jimmunol.168.10.4846. PMID 11994433.

[pmid9872321-14] Pitti RM, Marsters SA, Lawrence DA, Roy M, Kischkel FC, Dowd P et al. (December 1998). "Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer". Nature 396 (6712): 699–703. doi:10.1038/25387. PMID 9872321.

リンク元	「FasL protein」「CD95 ligand」「Fasリガンド」「Fas protein」「FasL」
拡張検索	「Fas ligand protein」
関連記事	「FAS」「F」

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Fas ligand

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