Pathway Map Details

Apoptosis and survival_Caspase cascade

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Object list (links open in MetaCore):

TRADD, AKT(PKB), FasL(TNFSF6), IGF-1, Caspase-2, Apaf-1, FADD, ICAD, TNF-R1, Lamin A/C, BAX, Bid, Lamin B, Caspase-9, NUMA1, RAIDD, IRS-1, Caspase-10, Bax, IGF-1 receptor, TNF-alpha, Caspase-8, Caspase-7, Bid = tBid, FasR(CD95), Caspase-6, PARP-1, RIPK1, Cytochrome C, Cytochrome C, Caspase-3, XIAP, DFF40 (CAD), Caspase-4, tBid


Caspase cascade

Caspases are the central components of the apoptotic response. The apoptotic caspases are generally divided into two classes: the initiator caspases, which include caspase-2, -8, -9 and -10 and the effector caspases, which include caspases-3, -6 and -7. All caspases are produced in cells as catalytically inactive zymogenes and must undergo proteolytic activation during apoptosis. Activation of effector caspases is carried out by an initiator caspases . Once activated, the effector caspases are responsible for the proteolytic cleavage of a broad spectrum of cellular targets, which ultimately leads to cell death [1].

The apoptotic response is activated through either the intrinsic or the extrinsic pathway, depending on the origin of the death stimuli.

The intrinsic pathway is triggered in response to a wide range of death stimulus that are generated from within the cell, such as oncogene activation and DNA damage.

The intrinsic pathway is mediated by mitochondria: In response to apoptotic stimuli several proteins, such as cytochrome c, are released from the intermembrane space of mitochondria into the cytoplasm. Cytochrome c binds to and activates the protein APAF1 in the cytoplasm that allows APAF1 to bind to ATP/dATP and to form the apoptosome, which mediates activation of caspase-9, thereby triggering a cascade of caspase activation.

The extrinsic pathway is initiated by binding of an extracellular death ligand, such as FasL and TNF-alpha, to its cell-surface death receptor, such as FasR and TNFR. Adaptor protein FADD, TRADD, RIDD transmit activating signal to effector caspases caspase-2, -8, and -10 [1].

Caspase-10 can function independently of caspase-8 in initiating Fas- and tumor necrosis factor-related apoptosis-inducing ligand-receptor-mediated apoptosis [2].

IGF-1 (insulin-like growth factor 1) exhibits strong anti-apoptotic activity. IGF-1 stimulates activation of AKT ( RAC serine/threonine-protein kinase) and AKT-induced inhibitory phosphorylation of caspase-9. Thereby IGF-1 inhibits caspase-9 mediated apoptosis [3].

Activation of caspase-2 occurs in a complex that contains death domain-containing protein PIDD and the adaptor protein RAIDD [4].

The extrinsic pathway 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 then triggers the release of mitochondrial proteins.

The conserved IAP family of proteins can potently inhibit the enzymatic activity of active caspases. Caspases-3, -7 and -9 are subject to inhibitory action of XIAP (X-linked inhibitor of apoptosis), which is a member of IAP family [5].

Caspase-3 and caspase-6 are necessary for cleavage of a large number of nuclear proteins essential for apoptosis-associated chromatin margination, DNA fragmentation, and nuclear collapse [6].


  1. Riedl SJ, Shi Y
    Molecular mechanisms of caspase regulation during apoptosis. Nature reviews. Molecular cell biology. 2004 Nov;5(11):897-907
  2. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ
    Caspase-10 is an initiator caspase in death receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 2001 Nov 20;98(24):13884-8
  3. Vincent AM, Feldman EL
    Control of cell survival by IGF signaling pathways. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 2002 Aug;12(4):193-7
  4. Tinel A, Tschopp J
    The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 2004 May 7;304(5672):843-6
  5. Tenev T, Zachariou A, Wilson R, Ditzel M, Meier P
    IAPs are functionally non-equivalent and regulate effector caspases through distinct mechanisms. Nature cell biology 2005 Jan;7(1):70-7
  6. Slee EA, Adrain C, Martin SJ
    Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. The Journal of biological chemistry 2001 Mar 9;276(10):7320-6