FAS signaling cascade
Death receptors such as FasR belong to a Tumour Necrosis Factor (TNF) superfamily of
receptors involved in proliferation, differentiation and apoptosis.
FasR is ubiquitously expressed in various tissues, but its
ligand FasL is expressed mainly in activated T lymphocytes
and natural killer cells. The binding of ligands to receptor induces receptor
trimerisation. Clustering on the plasma membrane is required to initiate apoptosis in
FasR have some splice variants and isoforms. Isoforms
which are missing the transmembrane domain (soluble form), or the intracellular domain,
(sFasR), can sequester FasL and
inhibit apoptosis. In addition to death receptors, there are decoy receptors (DcR).
DcR3 is a soluble receptor secreted by cells and binds with
Fas ligand (FasL). Decoy receptors possess functional
extracellular ligand binding domains but do not contain intracellular death domains and
cannot recruit adaptor proteins required for apoptosis. The principle function of decoy
receptors is modulating the sensitivity to death-receptor-mediated apoptosis in vivo.
DcR3 sequesters and inactivates the membrane-bound Fas
ligand on adjacent cells and prevents activation of Fas receptor
Activation of FasR lead to stimulation of several signal
cascades: activation of caspase cascade, activation of
intrinsic apoptotic pathway
mediated by mitochondria, and activation of JNK-cascade .
Upon binding FasL to FasR,
the receptor recruits a cytosolic adapter protein FADD
(Fas-associated death domain), FLASH (CASP8 associated
protein 2), and RAIDD (CASP2 and RIPK1 domain containing
adaptor with death domain) via RIPK1 (receptor
(TNFRSF)-interacting serine-threonine kinase 1). Adaptor proteins transmit
activating signal from the activated receptor
FasR to initiator caspases
caspase-2, -8, and
-10. Recruitment of caspases by adaptors to the plasma
membrane increases local concentration of these proteases and induces autocleavage and
activation of caspases. The complex formed by FasR,
FADD, Caspase-8, and possibly
other proteins is known as DISC (death-inducing signaling complex). CASP8 and FADD-like
apoptosis regulator (c-FLIP) share sequence homology with
Caspase-8 and can bind to the
FADD in competition with
Caspase-8. c-FLIP inhibits
Fas-mediated apoptosis when overexpressed in cells .
Activated initiator caspases cleave and activate effector
caspases-3, -6 and
-7. Once activated, the effector caspases are responsible
for the proteolytic cleavage of a broad spectrum of cellular targets, which ultimately
lead to cell death .
The extrinsic apoptotic pathway, induced by
FasR can crosstalk to the
intrinsic pathway through the caspase-8-mediated cleavage of
BID (a BH3-ONLY member of the BCL2 family of proteins),
which result to produce the pro-apoptotic tBID fragment
. In mitochondria, the tBID activates
BCL2-associated X protein (BAX) and thereby triggers the
release of mitochondrial proteins Cytochrome C, diablo
homolog (Smac/DIABLO), and HtrA-like serine
protease (HtrA2/OMI) .
These proteins reinforce the caspase cascade. Cytochrome
C induces oligomerization of Apaf-1 into
complexes which recruit and activate Caspases-9.
Smac/DIABLO and HtrA2/OMI
antagonize inhibitor of apoptosis proteins (XIAP,
IAP-1), a family of cellular caspase inhibitors .
FasR also stimulates the JNK signaling cascade.
FasR recruit mitogen-activated protein kinase kinase kinase
5 (ASK1) via adapter death-associated protein 6
(DAXX). Activation of ASK1
occur following recruitment to the DISC and subsequent JNK
activation is believed to promote apoptosis in cells .
JNK inhibit of action of B-cell lymphoma protein 2
(Bcl-2), which blocks the release of mitochondrial
PAK2 is cleaved into two defined fragments during
Fas-induced apoptosis and can activate JNK cascade .
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