The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:
1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption. <p> 2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.
Chen XQ, Fung YW, Yu AC.; ''Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes.''; PubMedEurope PMCScholia
Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM.; ''ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.''; PubMedEurope PMCScholia
Paulsen M, Ussat S, Jakob M, Scherer G, Lepenies I, Schütze S, Kabelitz D, Adam-Klages S.; ''Interaction with XIAP prevents full caspase-3/-7 activation in proliferating human T lymphocytes.''; PubMedEurope PMCScholia
Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q, Shi Y.; ''Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.''; PubMedEurope PMCScholia
Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y.; ''Mechanism of XIAP-mediated inhibition of caspase-9.''; PubMedEurope PMCScholia
Du C, Fang M, Li Y, Li L, Wang X.; ''Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.''; PubMedEurope PMCScholia
Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS.; ''XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs.''; PubMedEurope PMCScholia
Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMedEurope PMCScholia
Reingewertz TH, Shalev DE, Sukenik S, Blatt O, Rotem-Bamberger S, Lebendiker M, Larisch S, Friedler A.; ''Mechanism of the interaction between the intrinsically disordered C-terminus of the pro-apoptotic ARTS protein and the Bir3 domain of XIAP.''; PubMedEurope PMCScholia
Cheng TC, Hong C, Akey IV, Yuan S, Akey CW.; ''A near atomic structure of the active human apoptosome.''; PubMedEurope PMCScholia
Yuan S, Yu X, Topf M, Ludtke SJ, Wang X, Akey CW.; ''Structure of an apoptosome-procaspase-9 CARD complex.''; PubMedEurope PMCScholia
Denault JB, Békés M, Scott FL, Sexton KM, Bogyo M, Salvesen GS.; ''Engineered hybrid dimers: tracking the activation pathway of caspase-7.''; PubMedEurope PMCScholia
Wang L, Xing H, Tian Z, Peng L, Li Y, Tang K, Rao Q, Wang M, Wang J.; ''iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes.''; PubMedEurope PMCScholia
Li CQ, Robles AI, Hanigan CL, Hofseth LJ, Trudel LJ, Harris CC, Wogan GN.; ''Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53.''; PubMedEurope PMCScholia
Bhattacharya S, Ray RM, Johnson LR.; ''STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells.''; PubMedEurope PMCScholia
Bornstein B, Gottfried Y, Edison N, Shekhtman A, Lev T, Glaser F, Larisch S.; ''ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists.''; PubMedEurope PMCScholia
Arnoult D, Gaume B, Karbowski M, Sharpe JC, Cecconi F, Youle RJ.; ''Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization.''; PubMedEurope PMCScholia
Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S.; ''The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.''; PubMedEurope PMCScholia
Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A.; ''Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis.''; PubMedEurope PMCScholia
Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N.; ''Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.''; PubMedEurope PMCScholia
Zou H, Li Y, Liu X, Wang X.; ''An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9.''; PubMedEurope PMCScholia
Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D, Book-Melamed N, Timberg R, Duckett CS, Lechleider RJ, Steller H, Orly J, Kim SJ, Roberts AB.; ''A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.''; PubMedEurope PMCScholia
Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y, Alnemri ES.; ''A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.''; PubMedEurope PMCScholia
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC.; ''Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.''; PubMedEurope PMCScholia
Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMedEurope PMCScholia
Eskes R, Desagher S, Antonsson B, Martinou JC.; ''Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane.''; PubMedEurope PMCScholia
Lei K, Davis RJ.; ''JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.''; PubMedEurope PMCScholia
Patel S, George R, Autore F, Fraternali F, Ladbury JE, Nikolova PV.; ''Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax.''; PubMedEurope PMCScholia
Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H.; ''Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.''; PubMedEurope PMCScholia
Hershko T, Ginsberg D.; ''Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis.''; PubMedEurope PMCScholia
Yuan S, Topf M, Reubold TF, Eschenburg S, Akey CW.; ''Changes in Apaf-1 conformation that drive apoptosome assembly.''; PubMedEurope PMCScholia
Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y.; ''Structural and biochemical basis of apoptotic activation by Smac/DIABLO.''; PubMedEurope PMCScholia
Denault JB, Salvesen GS.; ''Human caspase-7 activity and regulation by its N-terminal peptide.''; PubMedEurope PMCScholia
Bellosillo B, Villamor N, López-Guillermo A, Marcé S, Bosch F, Campo E, Montserrat E, Colomer D.; ''Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia.''; PubMedEurope PMCScholia
Itahana K, Zhang Y.; ''Mitochondrial p32 is a critical mediator of ARF-induced apoptosis.''; PubMedEurope PMCScholia
Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMedEurope PMCScholia
Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y.; ''Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.''; PubMedEurope PMCScholia
Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ.; ''Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner.''; PubMedEurope PMCScholia
Chau BN, Cheng EH, Kerr DA, Hardwick JM.; ''Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1.''; PubMedEurope PMCScholia
Deveraux QL, Takahashi R, Salvesen GS, Reed JC.; ''X-linked IAP is a direct inhibitor of cell-death proteases.''; PubMedEurope PMCScholia
Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L, Chittenden T.; ''Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals.''; PubMedEurope PMCScholia
Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y.; ''Structural basis of IAP recognition by Smac/DIABLO.''; PubMedEurope PMCScholia
Ruffolo SC, Shore GC.; ''BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization.''; PubMedEurope PMCScholia
Fischer B, Coelho D, Dufour P, Bergerat JP, Denis JM, Gueulette J, Bischoff P.; ''Caspase 8-mediated cleavage of the pro-apoptotic BCL-2 family member BID in p53-dependent apoptosis.''; PubMedEurope PMCScholia
Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y.; ''Structural basis of caspase-7 inhibition by XIAP.''; PubMedEurope PMCScholia
Zou H, Henzel WJ, Liu X, Lutschg A, Wang X.; ''Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.''; PubMedEurope PMCScholia
Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ.; ''Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.''; PubMedEurope PMCScholia
Abhari BA, Davoodi J.; ''A mechanistic insight into SMAC peptide interference with XIAP-Bir2 inhibition of executioner caspases.''; PubMedEurope PMCScholia
Bratton SB, Walker G, Srinivasula SM, Sun XM, Butterworth M, Alnemri ES, Cohen GM.; ''Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes.''; PubMedEurope PMCScholia
Subramanian RR, Masters SC, Zhang H, Fu H.; ''Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis.''; PubMedEurope PMCScholia
Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X.; ''Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.''; PubMedEurope PMCScholia
Won J, Kim DY, La M, Kim D, Meadows GG, Joe CO.; ''Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis.''; PubMedEurope PMCScholia
Pathan N, Marusawa H, Krajewska M, Matsuzawa S, Kim H, Okada K, Torii S, Kitada S, Krajewski S, Welsh K, Pio F, Godzik A, Reed JC.; ''TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer.''; PubMedEurope PMCScholia
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.; ''Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.''; PubMedEurope PMCScholia
Khor TO, Gul YA, Ithnin H, Seow HF.; ''Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma.''; PubMedEurope PMCScholia
Martin MC, Allan LA, Mancini EJ, Clarke PR.; ''The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125.''; PubMedEurope PMCScholia
Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS, Jove R.; ''Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells.''; PubMedEurope PMCScholia
Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMedEurope PMCScholia
Alimonti JB, Shi L, Baijal PK, Greenberg AH.; ''Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition.''; PubMedEurope PMCScholia
Renatus M, Stennicke HR, Scott FL, Liddington RC, Salvesen GS.; ''Dimer formation drives the activation of the cell death protease caspase 9.''; PubMedEurope PMCScholia
Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMedEurope PMCScholia
Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Salvesen GS, Bode W.; ''Structural basis for the activation of human procaspase-7.''; PubMedEurope PMCScholia
Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A.; ''The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.''; PubMedEurope PMCScholia
Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Kronke M, Jurgensmeier JM.; ''XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells.''; PubMedEurope PMCScholia
del Peso L, González-García M, Page C, Herrera R, Nuñez G.; ''Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.''; PubMedEurope PMCScholia
Carpenter RL, Lo HW.; ''STAT3 Target Genes Relevant to Human Cancers.''; PubMedEurope PMCScholia
Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMedEurope PMCScholia
Antonsson B, Montessuit S, Sanchez B, Martinou JC.; ''Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells.''; PubMedEurope PMCScholia
Kang W, Hong SH, Lee HM, Kim NY, Lim YC, Le le TM, Lim B, Kim HC, Kim TY, Ashida H, Yokota A, Hah SS, Chun KH, Jung YK, Yang JK.; ''Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme.''; PubMedEurope PMCScholia
Thomsen ND, Koerber JT, Wells JA.; ''Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.''; PubMedEurope PMCScholia
Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ.; ''Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis.''; PubMedEurope PMCScholia
Song Z, Yao X, Wu M.; ''Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis.''; PubMedEurope PMCScholia
Shakeri R, Kheirollahi A, Davoodi J.; ''Apaf-1: Regulation and function in cell death.''; PubMedEurope PMCScholia
Yang QH, Du C.; ''Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells.''; PubMedEurope PMCScholia
Wilson AM, Morquette B, Abdouh M, Unsain N, Barker PA, Feinstein E, Bernier G, Di Polo A.; ''ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo.''; PubMedEurope PMCScholia
Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME.; ''14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.''; PubMedEurope PMCScholia
Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMedEurope PMCScholia
Sakai T, Liu L, Teng X, Mukai-Sakai R, Shimada H, Kaji R, Mitani T, Matsumoto M, Toida K, Ishimura K, Shishido Y, Mak TW, Fukui K.; ''Nucling recruits Apaf-1/pro-caspase-9 complex for the induction of stress-induced apoptosis.''; PubMedEurope PMCScholia
Yi X, Yin XM, Dong Z.; ''Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed.''; PubMedEurope PMCScholia
Kim HE, Du F, Fang M, Wang X.; ''Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1.''; PubMedEurope PMCScholia
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ.; ''tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.''; PubMedEurope PMCScholia
Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X.; ''A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.''; PubMedEurope PMCScholia
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
It is thought that due to its p53 dependence for expression, PUMA could function as a mediator of p53-induced apoptosis. Newly synthesized PUMA protein translocates to mitochondria and binds to BCL-2 and Bcl-X(L) through a BH3 domain.
At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-3' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-3' is present.
Permeabilization of the outer mitochondrial membrane by pro-apoptotic BCL2 family members BAK and BAX allows release of DIABLO (SMAC) from the mitochondrial intermembrane space into the cytosol (Arnoult et al. 2003). Binding of DIABLO (SMAC) to survivin leads to the inhibition of apoptosis (Song et al. 2003).
14-3-3 proteins bind BAD phosphorylated by activated AKT on serine residue S99 (corresponds to mouse Bad serine residue S136). Binding of 14-3-3 proteins to p-S99-BAD facilitates subsequent phosphorylation of BAD on serine residue S118 (corresponds to mouse serine S155), which disrupts binding of BAD to BCL2 proteins and promotes cell survival (Datta et al. 2000). Caspase-3 mediated cleavage of 14-3-3 proteins releases BAD and promotes apoptosis (Won et al. 2003). All known 14-3-3 protein isoforms (beta/alpha i.e. YWHAB, gamma i.e. YWHAG, zeta/delta i.e. YWHAZ, epsilon i.e. YWHAE, eta i.e. YWHAH, sigma i.e. SFN and theta i.e. YWHAQ) can interact with BAD and inhibit it (Subramanian et al. 2001, Chen et al. 2005).
After proteolytic activation, tBID is myristoylated by NMT-1 at an exposed glycine. N-myristoylation may enable the activated tBID to associate with the lipid components of the mitochondrial membrane.
Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-9' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-9' is present.
The caspase 8 -mediated cleavage of cytosolic, inactive p22 BID at internal Asp sites yields a major p15 and minor p13 and p11 fragments. After myristoylation, tBID translocates to mitochondria as an integral membrane protein.
tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAK induces intramembranous oligomerization leading to a pore for cytochrome c efflux (Wei et al. 2000).
During certain types of apoptosis, activated tBID (p15) induces a change in conformation of Bax which leads to the unmasking of its NH2-terminal domain. This change in confirmation usually results in the release of cytochrome c from mitochondria.
It was observed that cytosolic Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9.
Calcineurin, the Ca2+ activated protein phosphatase, dephosphorylates BAD, promoting dissociation of BAD from 14-3-3 proteins and the translocation of BAD to the outer mitochondrial membrane (Wang et al. 1999).
MAPK8 (JNK) phosphorylates BCL2L11 (BIM) on a DLC-binding motif (DKSTQTP), involved in dynein (DYNLL2 i.e. DLC1) binding and sequestration of BCL2L11 (BIM) to the cytoskeleton. Phosphorylated BCL2L11 dissociates from dynein. Three sites in BCL2L11 match the JNK consensus: S44, T56 and S58 in BCL2L11 isoform BimL (these residues correspond to S104, T116 and S118 in BCL2L11 isoform BimEL), and all sites appear to be phosphorylated by MAPK8 (JNK) both in vitro and in vivo (Lei and Davis 2003).
MAPK8 (JNK) phosphorylates BMF on a DLC binding motif DKATQTLSP involved in interaction with dynein DYNLL2 (DLC2), which sequesters BMF to the cytoskeleton. Phosphorylated BMF dissociates from dynein. Two JNK consensus sites exist in BMF: S74 and S77 (Lei and Davis 2003).
At the beginning of this reaction, 1 molecule of 'XIAP:Caspase-7', and 1 molecule of 'SMAC' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-7' is present.
Binding of DIABLO (SMAC) to the BIR2 domain of XIAP competes with binding of caspase-7 to the same domain of BIR2. As DIABLO has a higher affinity for the BIR2 domain than caspase-7, DIABLO (SMAC) binding to XIAP results in the liberation of caspase-7 (Huang et al. 2001).
BH3-only proteins (tBid, BIM, PUMA, BAD, NOXA) associate with and inactivate anti-apoptotic protein Bcl-XL( Yi et al., 2003; Puthalakath et al., 1999; Nakano and Vousden, 2001; Wang et al., 1999; Oda et al., 2000). The interactions of NOXA with Bcl-XL are inferred from experiments performed in mice (Oda et al., 2000).
Bcl-2 interacts with tBid (Yi et al. 2003), BIM (Puthalakath et al. 1999), PUMA (Nakano and Vousden 2001), NOXA (Oda et al. 2000), BAD (Yang et al. 2005), BMF (Puthalakath et al. 2001), resulting in inactivation of BCL2.
Once integrated in the outer mitochondrial membrane, BAX forms oligomeric complexes which play an important role in cytochrome C release (Antonsson et al. 2001)
Once activated BAK insterts in the outer mitochondrial membrane, it oligomerizes and these oligomeric BAK complexes are important for the cytochrome C efflux (Ruffolo and Shore 2003).
Permeabilization of the outer mitochondrial membrane by pro-apoptotic BCL2 family proteins, such as BAK and BAX, allows cytochrome c eflux from the mitochondrial intermembrane space into the cytosol (Arnoult et al. 2003).
tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAK induces intramembranous oligomerization leading to a pore for cytochrome c efflux (Wei et al. 2000).
Once BCL2L11 (BIM) dissociates from the cytoskeleton, it translocates to the outer mitochondrial membrane where it associates with BCL2 (Puthalakath et al. 1999).
1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption. <p> 2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.
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DataNodes
Apaf-1 ATP
Procaspase-9XIAP
Caspase-3XIAP
Caspase-7XIAP
Caspase-9Annotated Interactions
Apaf-1 ATP
Procaspase-9This reaction takes place in the 'cytosol'.
This reaction takes place in the 'cytosol'.
This reaction takes place in the 'cytosol'.