CD95 APO-1(apoptosis antigen 1), FAS, TNFRSF6(tumor necrosis factor receptor superfamily,member 6), APT1
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
B Cell
Monocyte
Neutrophil
Fibroblast
T Cell
Liver
Heart
Lung
Thymus
Kidney
Ovary
45 / 45
90 / 90
200 / 200

Expression
CD95 is expressed, typically at high levels, on activated T and B cells.  It is also expressed on monocytes, neutrophils, fibroblasts and cell lines.  Mouse CD95 mRNA is also found in liver, heart, lung, thymus, ovary and kidney.  In contrast to CD95 Fas, CD178 FasL is mainly restricted to activated T lymphocytes and is induced rapidly.  FasL mRNA has been identified in rodent testis and eye and expression is confirmed in the latter with a mAb.


Structure
MOLECULAR FAMILY NAME: Belongs to the tumor necrosis factor receptor family.

CD95 is a single-chain type-1 glycoprotein.  It contains a 16 aa signal sequence, a 157 aa
extracellular domain which contains 3 cysteine-rich domains and 2 O-glycosylation sites, a 320 aa transmembrane and a 214-295 aa proline-rich cytoplasmic domain which contains a death domain and a consensus SH3 binding motif.  Like other members of this TNFR superfamily, CD95 is expressed as a trimer with the similarity to the TNF being in the C-terminal extracellular region and occur in a soluble form.
  
MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Activated T cell 45, 90 >200 kDa 45 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 6 isoforms, one soluble cell membrane and 5 secreted isoforms.  The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. 


POST-TRANSLATIONAL MODIFICATION

There are 2 serine/threonine glycosylation sites at the extracellular region and phosphorylation.

Ligands
The extracellular region of CD95 binds to CD178 CD95L).  Intracellular molecules isolated by the yeast 2 hybrid technique as interacting with the CD95 cytoplasmic domain contain a "death domain" and include MORT/FADD.  CD178 binding to CD95 recruits an interleukin-converting enzyme (ICE)-related protease via its association with MORT.  The C-terminal of CD95 has 15 aa and associates with a protein tyrosine phosphatase.

LIGANDS AND MOLECULES ASSOCIATED WITH CD95
Molecule Comment
Fas ligand Fas ligand CD178 belongs to the tumor necrosis factor family



Function
CD178 (CD95L) binding to CD95 induces apoptosis-inducing signals  in activated mature lymphocytes, thus has a role in maintaining peripheral tolerance but does not appear critical in development.  The binding result in dimeriztion of two trimers and high levels of oligomerization.  Once activated, the FADD protein binds to the CD95 cytoplasmic death domain to form the dead inducing signal complex which triggers a capase-dependent cascade that results in cell death.  Autoimmune disease in lpr mice and in humans is associated with mutations in CD95.  The mechanism of killing by CD95 is thought to involve ICE and ICE-like proteases.  CD178 on cytotoxic T cells can induce cytolysis of target cells expressing CD95.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD95 IN INTACT ANIMAL

Defects in CD95 are a cause of autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome (CSS), which involves hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly.  CD95 is found in the serum from patients with adrenal tumors.  The expression of CD95 and CD178 is present in the esophageal tissue mucosa and carcinomas.  Expression is also significantly increased in neonates with neuron necrosis.  lpr/lpr mutant mice have a defect and do not express CD95 and develop lymphadenopathy and systemic autoimmune disease.  One of receptor molecules mediates apoptosis of targets by cytotoxic T cells.

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD95: No information.

SUBSTRATES
Molecule Comment
FADD/MORT1 Association of FADD through death domain-death domain interaction of Fas and FADD
FLICE/MACH-1/caspase-8 Another domain of FADD associates with FLICE/MACH-1, a member of caspase, and then FLICE/MACH-1 is activated

ENZYMES WHICH MODIFY CD95: No information.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 355P25445
MouseA46484P25446M83649
MouseP41047S76752
RatP36940U03470
Antibodies
7C11   View Reactivity
DX2   View Reactivity
DX3   View Reactivity
LOB3/17   View Reactivity
UB2   View Reactivity
ZB4   View Reactivity

Revised June 25, 2008


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