Apoptosis - Homo sapiens (human)

Curator(s): Peter D'Adamo

Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis.    
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Apoptosis - Homo sapiens (human) cluster_node40 CELL MEMBRANE node1 Fas-L Fas (TNF receptor superfamily,member 6) FAS node1->FAS node2 2 TRAIL TRAIL->node2 TRAIL node8 TRAIL-R TRAIL->node8 node3 21 tumor necrosis factor TNF TNF->node3 TNF node10 TNF-R1 TNF->node10 node4 5 node5 IL-1 node5->node4 IL-1 node11 IL-1R node5->node11 node6 1 node7 1 node9 2 Fas (TNFRSF6)-associated via death domain FADD caspase 10,apoptosis-related cysteine peptidase CASP10 FADD->CASP10 caspase 8,apoptosis-related cysteine peptidase CASP8 FADD->CASP8 node12 TRADD FADD node12->CASP10 node12->CASP8 node13 TRADD RIP1 TRAF2 NIK node13->NIK node14 2 node15 MYD88 IRAK node15->node14 MYD88~IRAK node15->NIK node16 1 CASP10->node16 CASP10 caspase 3,apoptosis-related cysteine peptidase CASP3 CASP10->CASP3 Type 1 node17 6 CASP8->node17 CASP8 BH3 interacting domain death agonist BID CASP8->BID Type 2 CASP8->CASP3 node18 1 NIK->node18 NIK IKK NIK->IKK +p FLIP FLIP->FADD FLIP->node12 node19 8 IKK->node19 IKK IKBA IKK->IKBA +p Mitochondria BID->Mitochondria node22 2 Mitochondria->node22 node20 21 node21 Bcl2/XL node21->node20 Bcl2/XL node21->node22 CytC node22->CytC AIF AIF->node22 DNA Fragmentation AIF->DNA Fragmentation node23 2 CytC->node23 CytC caspase 9,apoptosis-related cysteine peptidase CASP9 CytC->CASP9 apoptotic peptidase activating factor 1 APAF1 APAF1->CASP9 node24 9 CASP9->node24 CASP9 caspase 7,apoptosis-related cysteine peptidase CASP7 CASP9->CASP7 CASP9->CASP3 node25 2 IAP IAP->CASP9 IAP->node25 IAP IAP->CASP7 IAP->CASP3 caspase 6,apoptosis-related cysteine peptidase CASP6 IAP->CASP6 Survival IAP->Survival node26 5 CASP7->node26 CASP7 DNA fragmentation factor,45kDa,alpha polypeptide DFFA CASP7->DFFA Caspase Substrate Cleavage CASP7->Caspase Substrate Cleavage node27 26 CASP3->node27 CASP3 CASP3->DFFA CASP3->CASP6 CASP3->Caspase Substrate Cleavage DNA fragmentation factor,40kDa,beta polypeptide (caspase-activated DNase) DFFB DFFA->DFFB Degradation DFFA->Degradation DFFB->DNA Fragmentation CASP6->Caspase Substrate Cleavage Apoptosis DNA Fragmentation->Apoptosis Caspase Substrate Cleavage->Apoptosis node28 6 IKBA->Degradation IKBA->node28 IKBA NFKB IKBA->NFKB node29 32 NFKB->node29 NFKB DNA survival genes NFKB->DNA survival genes DNA survival genes->node21 DNA survival genes->IAP nerve growth factor (beta polypeptide) NGF TrkA NGF->TrkA interleukin 3 (colony-stimulating factor,multiple) IL3 node37 3 IL3->node37 IL3R IL3->IL3R node30 12 PI3K PI3K->node30 PI3K node32 Akt/PKB PI3K->node32 node31 17 node32->IKK +p node32->node31 Akt/PKB BCL2-associated agonist of cell death BAD node32->BAD +p node33 2 BAD->Apoptosis BAD->node33 BAD BAD->Survival node34 1 PKA PKA->BAD +p PKA->node34 PKA cAMP cAMP->PKA node35 5 tumor protein p53 TP53 TP53->node35 TP53 p53 signaling pathway TP53->p53 signaling pathway node36 21 B-cell CLL/lymphoma 2 BCL2 BCL2->TP53 BCL2->node36 BCL2 DNA death genes p53 signaling pathway->DNA death genes DNA death genes->Apoptosis BCL2-associated X protein BAX node37->BAX node38 16 BAX->Apoptosis BAX->node38 BAX ER Stress Cn ER Stress->Cn Calpain ER Stress->Calpain Cn->BAD -p node39 1 Calpain->node39 Calpain caspase 12 (gene/pseudogene) CASP12 Calpain->CASP12 CASP12->CASP3 ataxia telangiectasia mutated ATM ATM->TP53 +p Cell cycle DNA damage Cell cycle->DNA damage DNA damage->ATM FAS->node6 FAS FAS->FADD node11->node12 node11->node15 IL3R->PI3K IL3R->cAMP IL3R->node37 TrkA->PI3K node10->node9 TNF-R1 node10->node12 node10->node13 node8->node7 TRAIL-R node8->FADD print "