Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Apoptosis and survival FAS signaling cascades

Log In to Post A Comment

Apoptosis and survival FAS signaling cascades

FAS signaling cascade

Death receptors such as FasR belong to a Tumour Necrosis Factor (TNF) superfamily ofreceptors involved in proliferation, differentiation and apoptosis. FasR isubiquitously expressed in various tissues, but its ligand FasL is expressed mainlyin activated T lymphocytes and natural killer cells. The binding of ligands to receptorinduces receptor trimerisation. Clustering on the plasma membrane is required to initiateapoptosis in cells.

FasR have some splice variants and isoforms. Isoforms which are missing thetransmembrane domain (soluble form), or the intracellular domain, ( sFasR), cansequester FasL and inhibit apoptosis. In addition to death receptors, there aredecoy receptors (DcR). DcR3 is a soluble receptor secreted by cells and binds withFas ligand ( FasL). Decoy receptors possess functional extracellular ligandbinding domains but do not contain intracellular death domains and cannot recruit adaptorproteins required for apoptosis. The principle function of decoy receptors is modulatingthe sensitivity to death-receptor-mediated apoptosis in vivo. DcR3 sequesters andinactivates the membrane-bound Fas ligand on adjacent cells and prevents activation ofFas receptor ( FasR ).

Activation of FasR lead to stimulation of several signal cascades: activationof caspase cascade, activation of intrinsic apoptotic pathway mediated bymitochondria, and activation of JNK-cascade [1].

Upon binding FasL to FasR, the receptor recruits a cytosolic adapterprotein FADD (Fas-associated death domain), FLASH (CASP8 associated protein2), and RAIDD ( CASP2 and RIPK1 domain containing adaptor with death domain) viaRIPK1 (receptor (TNFRSF)-interacting serine-threonine kinase 1). Adaptor proteinstransmit activating signal from the activated receptor FasR to initiator caspasescaspase-2, -8, and -10. Recruitment of caspases by adaptors to theplasma membrane increases local concentration of these proteases and induces autocleavageand activation of caspases. The complex formed by FasR, FADD,Caspase-8, and possibly other proteins is known as DISC (death-inducing signalingcomplex). CASP8 and FADD-like apoptosis regulator ( c-FLIP ) share sequencehomology with Caspase-8 and can bind to the FADD in competition withCaspase-8. c-FLIP inhibits Fas-mediated apoptosis when overexpressed incells [2].

Activated initiator caspases cleave and activate effector caspases-3,-6 and -7. Once activated, the effector caspases are responsible for theproteolytic cleavage of a broad spectrum of cellular targets, which ultimately lead tocell death [3].

The extrinsic apoptotic pathway, induced by FasR can crosstalk to theintrinsic pathway through the caspase-8-mediated cleavage of BID (aBH3-ONLY member of the BCL2 family of proteins), which result to produce thepro-apoptotic tBID fragment [4]. In mitochondria, the tBIDactivates BCL2-associated X protein ( BAX ) and thereby triggers the release ofmitochondrial proteins Cytochrome C, diablo homolog ( Smac/DIABLO), andHtrA-like serine protease (HtrA2/OMI) [5].

These proteins reinforce the caspase cascade. Cytochrome C inducesoligomerization of Apaf-1 into complexes which recruit and activateCaspases-9. Smac/DIABLO and HtrA2/OMI antagonize inhibitor ofapoptosis proteins ( XIAP, IAP-1 ), a family of cellular caspaseinhibitors [6].

FasR also stimulates the JNK signaling cascade. FasR recruitmitogen-activated protein kinase kinase kinase 5 ( ASK1 ) via adapterdeath-associated protein 6 ( DAXX ). Activation of ASK1 occur followingrecruitment to the DISC and subsequent JNK activation is believed to promoteapoptosis in cells [7]. JNK inhibit of action of B-cell lymphomaprotein 2 ( Bcl-2 ), which blocks the release of mitochondrial proteins.

PAK2 is cleaved into two defined fragments during Fas-induced apoptosis andcan activate JNK cascade [8].