1. Activated Tissue Transglutaminase
Caspase Cascade
Fas
Ca2+
2009
ProteinLounge.com C
Calcium Channel
GranzymeB
TNF
GRB
TNFR
F a s L
Perforin
Perforin
GRB
ER Stress
RAIDD
RIP2
Daxx
TRADD
Caspase2
Ca2+
FADD
Caspase12
Procaspase8
FADD
Caspase2
NIK
TRADD
Caspase8
Calpain
JNK
RAIDD
Review:
Caspases are a family of cysteine proteases that act in concert in a cascade triggered by apoptosis signaling. The culmination of this cascade is the cleavage of a number of proteins in the cell, followed by cell disassembly, cell death, and, ultimately, the phagocytosis and removal of the cell debris. The Caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria (Ref.1). The pathway leading to Caspase activation varies according to the apoptotic stimulus. Initiator Caspases (including 8, 9, 10 and 12) are closely coupled to pro-apototic signals. Pro-apoptotic stimuli include the FasL (Fas Ligand), TNF (Tumor Necrosis Factor), Granzyme-B, GRB (Growth Factor Receptor-Bound Protein), DNA damage, Ca2+ (Calcium) channels and ER (Endoplasmic Reticulum) stress. Once activated, these Caspases cleave and activate downstream effector Caspases (including 3, 6 and 7). Caspase8 cleaves BID (BH3 Interacting Death Domain). tBID (Truncated BID) disrupts the outer mitochondrial membrane to cause release of the pro-apoptotic factors CytoC (Cytochrome-C) which is crucial for activating pro-Caspase9. CytoC that is released from the intermembrane space binds to APAF1 (Apoptotic Protease Activating Factor-1), which recruits Caspase9 and in turn can proteolytically activate Caspase3. SMAC (Second Mitochondria-Derived Activator of Caspase)/DIABLO is also released from the mitochondria along with CytoC during apoptosis, and it functions to promote caspase activation by inhibiting IAP (Inhibitor of Apoptosis) family proteins. ER stress leads to the Ca2+-mediated activation of Caspase12 (Ref.2).
Fas and the TNFR (TNF Receptor) activate Caspases8 and 10. Cell death caused by activation of the TNFR or Fas receptors is brought about by the recruitment of the adaptor protein FADD (Fas Associated Death Domain). In the case of the TNFR1, FADD recruitment requires prior binding of TRADD (TNFR-Associated Death Domain Protein). FADD in turn recruits ProCaspase8. The TNFR1 receptor can also mediate activation of Caspase2 via the recruitment of a death-inducing signaling complex. In this case RIP (Receptor-Interacting Protein) acts as an adaptor for the recruitment of RAIDD (RIP-Associated ICH-1/CED-3-homologous protein with a Death Domain), which subsequently binds to ProCaspase2. TNFR also activates Caspase3, 6,7 via TRADD, TRAF2 (TNF Receptor-Associated Factor-2) and RICK (RIP-like Interacting Clarp Kinase). TNF not only induces apoptosis by activating Caspase8 and 10, but can also inhibit apoptosis signaling via NF-KappaB (Nuclear Factor-KappaB), which induces the expression of IAP, an inhibitor of Caspases3, 7 and 9 (Ref.3).
GRB (Growth Factor Receptor-Bound Protein), Granzyme B and perforin proteins released by cytotoxic T-Cells induce apoptosis in target cells, forming transmembrane pores, and triggering apoptosis, perhaps through cleavage of Caspases, although Caspase-independent mechanisms of Granzyme-B mediated apoptosis have been suggested (Ref.4). After activation, down stream Caspases cleave cytoskeletal and nuclear proteins (structural, signaling proteins or kinases) like PARP (Poly ADP-Ribose Polymerase), DNA-PK (DNA-Dependent Protein Kinase), Rb (Retino Blastoma Tumor Supressor Protein), PAK1 (p21-Activated Kinase-1), GDID4, Fodrin, Lamin-A, Lamin-B1, Lamin-B2, thus inducing apoptosis. Caspase3 cleaves ICAD (Inhibitor of CAD) to free CAD (Caspase-Activated DNase) to cause DNA fragmentation. The events culminating in Caspase activation and the subsequent disassembly of the cell are the subject of intense study because of their role in many neurodegenerative disorders such as Parkinson's and Alzheimer’s diseases, autoimmune disorders, and tumorigenesis.
References:
1. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES.
Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization.
Mol Cell Jun;1(7):
PubMed ID:
2. Pirnia F, Schneider E, Betticher DC, Borner MM.
Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway.
Cell Death Differ Sep;9(9):
PubMed ID:
3. Swanton E, Savory P, Cosulich S, Clarke P, Woodman P.
Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts.
Oncogene Mar 11;18(10):
PubMed ID:
4. Pinkoski MJ, Heibein JA, Barry M, Bleackley RC.
Nuclear translocation of granzyme B in target cell apoptosis.
Cell Death Differ Jan;7(1):17-24.
PubMed ID:
Caspase10
TRADD
Sphingo- myelinase
Caspase8
NF-kB
BID
RICK
TRAF2
Caspase1
Activated Tissue Transglutaminase
Caspase2
Ceramide
tBID
SMAC/ DIABLO
CIAP
Kinase
CytoC
Caspase 3,6,7
CIAP
CRMA
CytoC
APAF1
PAK1
Caspase9
BAD
CLEAVAGE OF DEATH SUBSTRATES
Cell Survival
Lamin-A Rb
Lamin-B1
Lamin-A
Lamin-B2
ICAD
D4-GDI
CAD
DNA-PK
PARP
ICAD Cleaved
CAD
Apoptosis
DNA Fragmentation
Apoptosis