BioPAX pathway converted from "Apoptosis" in the Reactome database. Apoptosis Apoptosis Apoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and membrane blebbing characterize apoptosis in general. Mitochondria remain morphologically unchanged. In 1972 Kerr et al introduced the concept of apoptosis as a distinct form of "cell-death", and the mechanisms of various apoptotic pathways are still being revealed today. <BR>The two principal pathways of apoptosis are (1) the Bcl-2 inhibitable or intrinsic pathway induced by various forms of stress like intracellular damage, developmental cues, and external stimuli and (2) the caspase 8/10 dependent or extrinsic pathway initiated by the engagement of death receptors<BR> The caspase 8/10 dependent or extrinsic pathway is a death receptor mediated mechanism that results in the activation of caspase-8 and caspase-10. Activation of death receptors like Fas/CD95, TNFR1, and the TRAIL receptor is promoted by the TNF family of ligands including FASL (APO1L OR CD95L), TNF, LT-alpha, LT-beta, CD40L, LIGHT, RANKL, BLYS/BAFF, and APO2L/TRAIL. These ligands are released in response to microbial infection, or as part of the cellular, humoral immunity responses during the formation of lymphoid organs, activation of dendritic cells, stimulation or survival of T, B, and natural killer (NK) cells, cytotoxic response to viral infection or oncogenic transformation. <BR> The Bcl-2 inhibitable or intrinsic pathway of apoptosis is a stress-inducible process, and acts through the activation of caspase-9 via Apaf-1 and cytochrome c. The rupture of the mitochondrial membrane, a rapid process involving some of the Bcl-2 family proteins, releases these molecules into the cytoplasm. Examples of cellular processes that may induce the intrinsic pathway in response to various damage signals include: auto reactivity in lymphocytes, cytokine deprivation, calcium flux or cellular damage by cytotoxic drugs like taxol, deprivation of nutrients like glucose and growth factors like EGF, anoikis, transactivation of target genes by tumor suppressors including p53.<BR> In many non-immune cells, death signals initiated by the extrinsic pathway are amplified by connections to the intrinsic pathway. The connecting link appears to be the truncated BID (tBID) protein a proteolytic cleavage product mediated by caspase-8 or other enzymes. Extrinsic Pathway for Apoptosis Extrinsic Pathway for Apoptosis Known as the "death receptor pathway" the extrinsic or caspase 8/10 dependent pathway is activated by ligand binding. The "death receptors" are specialized cell-surface receptors including Fas/CD95, tumor necrosis factor-alpha (TNF-alpha) receptor 1, and two receptors, DR4 and DR5, that bind to the TNF-alpha related apoptosis-inducing ligand (TRAIL). The extrinsic and intrinsic pathways unite in the activation of Caspase-3, though the two pathways communicate through the pro-apoptotic Bcl-2 family member Bid before uniting at the shared activation of Caspase-3. Death Receptor Signalling Death Receptor Signalling The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD) FasL/ CD95L signaling FasL/ CD95L signaling The Fas family of cell surface receptors initiate the apototic pathway through interaction with the external ligand, FasL. The cytoplasmic domain of Fas interacts with a number of molecules in the transduction of the external signal to the cytoplasmic side of the cell membrane. The most notable cytoplasmic domain is the Death Domain (DD) that is involved in recruiting the FAS-associating death domain-containing protein (FADD). This interaction drives downstream events. FASL binds FAS Receptor FASL binds FAS Receptor At the beginning of this reaction, 1 molecule of 'FASL', and 1 molecule of 'FAS Receptor' are present. At the end of this reaction, 1 molecule of 'FASL:FAS Receptor monomer' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 extracellular region GO 0005576 UniProt:P48023-1 Tumor necrosis factor ligand superfamily member 6 (FAS antigen ligand) (Apoptosis antigen ligand) (APTL) (CD178 antigen) FASL TNFSF6 APT1LG1 FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that transduces the apoptotic signal into cells. May be involved in cytotoxic T cell mediated apoptosis and in T cell development. TNFRSF6/FAS-mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T cells, or both. Binding to the decoy receptor TNFRSF6B/DcR3 modulates its effects. SUBUNIT: Homotrimer (Probable). SUBCELLULAR LOCATION: Type II membrane protein. May be released into the extracellular fluid, probably by cleavage form the cell surface. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=P48023-1; Sequence=Displayed; Name=2; IsoId=P48023-2; Sequence=VSP_006443, VSP_006444; PTM: N-glycosylated. PTM: The soluble form derives from the membrane form by proteolytic processing. DISEASE: Defects in TNFSF6 are a cause of autoimmune lymphoproliferative syndrome (ALPS) [MIM:601859]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly. SIMILARITY: Belongs to the tumor necrosis factor family. DATABASE: NAME=PROW; NOTE=PROW 2:59-69(2001); WWW="http://www.ncbi.nlm.nih.gov/prow/guide/333879674_g.htm". Reactome http://www.reactome.org Homo sapiens NCBI_taxonomy 9606 UniProt P48023 1 plasma membrane GO 0005886 UniProt:P25445-1 Tumor necrosis factor receptor superfamily member 6 precursor (FASL receptor) (Apoptosis-mediating surface antigen FAS) (Apo-1 antigen) (CD95 antigen) FAS TNFRSF6 APT1 FAS1 FUNCTION: Receptor for TNFSF6/FASL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death- inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. FAS- mediated apoptosis may have a role in the induction of peripheral tolerance, in the antigen-stimulated suicide of mature T-cells, or both. The secreted isoforms 2 to 6 block apoptosis (in vitro). SUBUNIT: Binds DAXX (By similarity). Binds RIPK1 and FAIM2. SUBCELLULAR LOCATION: Type I membrane protein (isoform 1); Secreted (isoforms 2 to 6). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=6; Name=1; IsoId=P25445-1; Sequence=Displayed; Name=2; Synonyms=del2, D; IsoId=P25445-2; Sequence=VSP_006481, VSP_006482; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=3; Synonyms=del3, E; IsoId=P25445-3; Sequence=VSP_006483, VSP_006484; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=4; Synonyms=B; IsoId=P25445-4; Sequence=VSP_006485, VSP_006486; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=5; Synonyms=C; IsoId=P25445-5; Sequence=VSP_006487, VSP_006488; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=6; Synonyms=TMdel, A; IsoId=P25445-6; Sequence=VSP_006489; TISSUE SPECIFICITY: Isoform 1 and isoform 6 are expressed at equal levels in resting peripheral blood mononuclear cells. After activation there is an increase in isoform 1 and decrease in the levels of isoform 6. DOMAIN: Contains a death domain involved in the binding of FADD, and maybe to other cytosolic adapter proteins. DISEASE: Defects in TNFRSF6 are a cause of autoimmune lymphoproliferative syndrome (ALPS) [MIM:601859, 183350]; also known as Canale-Smith syndrome (CSS). ALPS is a childhood syndrome involving hemolytic anemia and thrombocytopenia with massive lymphadenopathy and splenomegaly. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 3 TNFR-Cys repeats. DATABASE: NAME=PROW; NOTE=CD guide CD95 entry; WWW="http://www.ncbi.nlm.nih.gov/prow/cd/cd95.htm". UniProt P25445 1 FASL:FAS Receptor monomer [plasma membrane] FASL:FAS Receptor monomer 1 1 Reactome 75244 http://www.reactome.org 7530336 Pubmed 1995 Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas Brunner, T Mogil, RJ LaFace, D Yoo, NJ Mahboubi, A Echeverri, F Martin, SJ Force, WR Lynch, DH Ware, CF Nature 373:441-4 GO 0008624 GO biological process Trimerization of the FASL:FAS receptor complex Trimerization of the FASL:FAS receptor complex At the beginning of this reaction, 3 molecules of 'FASL:FAS Receptor monomer' is present. At the end of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer' is present.<br><br> This reaction takes place in the 'cell'.<br> 3 1 FASL:FAS Receptor Trimer [plasma membrane] FASL:FAS Receptor Trimer 3 Reactome 71050 http://www.reactome.org 8521815 Pubmed 1995 Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor Kischkel, FC Hellbardt, S Behrmann, I Germer, M Pawlita, M Krammer, PH Peter, ME EMBO J 14:5579-88 FasL:Fas binds FADD FasL:Fas binds FADD At the beginning of this reaction, 1 molecule of 'FADD', and 1 molecule of 'FASL:FAS Receptor Trimer' are present. At the end of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer:FADD complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 cytosol GO 0005829 UniProt:Q13158 FADD protein (FAS-associating death domain-containing protein) (Mediator of receptor induced toxicity) MORT1 FADD FUNCTION: Apoptotic adaptor molecule that recruits caspase-8 or caspase-10 to the activated Fas (CD95) or TNFR-1 receptors. The resulting aggregate called the death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation. Active caspase-8 initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. SUBUNIT: Interacts with CFLAR, PEA15 and MBD4. TISSUE SPECIFICITY: Expressed in a wide variety of tissues, except for peripheral blood mononuclear leukocytes. DOMAIN: Contains a death domain involved in the binding of the corresponding domain within Fas receptor. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 1 death effector (DED) domain. UniProt Q13158 1 FASL:FAS Receptor Trimer:FADD complex [plasma membrane] FASL:FAS Receptor Trimer:FADD complex 1 1 Reactome 83650 http://www.reactome.org 7536190 Pubmed 1995 A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain Boldin, MP Varfolomeev, EE Pancer, Z Mett, IL Camonis, JH Wallach, D J Biol Chem 270:7795-8 FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-8 FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-8 At the beginning of this reaction, 1 molecule of 'Caspase-8 precursor ', and 1 molecule of 'FASL:FAS Receptor Trimer:FADD complex' are present. At the end of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 UniProt:Q14790-1 Caspase-8 precursor (EC 3.4.22.-) (CASP-8) (ICE-like apoptotic protease 5) (MORT1-associated CED-3 homolog) (MACH) (FADD-homologous ICE/CED-3-like protease) (FADD-like ICE) (FLICE) (Apoptotic cysteine protease) (Apoptotic protease Mch-5) (CAP4) CASP8 MCH5 FUNCTION: Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoforms 5, 6, 7 and 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. SUBUNIT: Heterodimer of a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=9; Name=1; Synonyms=Alpha-1; IsoId=Q14790-1; Sequence=Displayed; Name=2; Synonyms=Alpha-2, MCH5-beta; IsoId=Q14790-2; Sequence=VSP_000810; Name=3; Synonyms=Alpha-3; IsoId=Q14790-3; Sequence=VSP_000813; Name=4; Synonyms=Alpha-4; IsoId=Q14790-4; Sequence=VSP_000809, VSP_000810; Name=5; Synonyms=Beta-1; IsoId=Q14790-5; Sequence=VSP_000814, VSP_000815; Name=6; Synonyms=Beta-2; IsoId=Q14790-6; Sequence=VSP_000811, VSP_000812; Name=7; Synonyms=Beta-3, 8L; IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=8; Synonyms=Beta-4; IsoId=Q14790-8; Sequence=VSP_000810, VSP_000816, VSP_000817; Name=9; Synonyms=8L; IsoId=Q14790-9; Sequence=VSP_000808; TISSUE SPECIFICITY: Isoforms 1, 5 and 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus, and liver. Barely detectable in brain, testis, and skeletal muscle. DOMAIN: Isoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex. PTM: Generation of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. DISEASE: Defects in CASP8 are the cause of caspase 8 deficiency (CASP8D) [MIM:607271], a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). CASP8D is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T lymphocytes, B lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. SIMILARITY: Belongs to the peptidase C14 family. SIMILARITY: Contains 2 death effector (DED) domains. CAUTION: Ref.1 (CAA66858 and CAA66859) sequences differ from that shown; further sequencing indicated that the C-terminus was different from that originally shown. UniProt Q14790 1 1 FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC [plasma membrane] FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC 1 1 Reactome 83586 http://www.reactome.org 8681376 Pubmed 1996 Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death Boldin, MP Goncharov, TM Goltsev, YV Wallach, D Cell 85:803-15 FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-10 FASL:FAS Receptor Trimer:FADD complex binds pro-Caspase-10 At the beginning of this reaction, 1 molecule of 'Caspase-10 precursor ', and 1 molecule of 'FASL:FAS Receptor Trimer:FADD complex' are present. At the end of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer:FADD:pro-Caspase-10' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 UniProt:Q92851-1 Caspase-10 precursor (EC 3.4.22.-) (CASP-10) (ICE-like apoptotic protease 4) (Apoptotic protease Mch-4) (FAS-associated death domain protein interleukin-1B-converting enzyme 2) (FLICE2) MCH4 CASP10 FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Recruited to both Fas- and TNFR-1 receptors in a FADD dependent manner. May participate in the granzyme B apoptotic pathways. Cleaves and activates caspase- 3, -4, -6, -7, -8, and -9. Hydrolyzes the small- molecule substrates, Tyr-Val-Ala-Asp-|-AMC and Asp-Glu-Val-Asp-|-AMC. FUNCTION: Isoform C is proteolytically inactive. SUBUNIT: Heterodimer of a 23/17 kDa (p23/17) depending on the splicing events and a 12 kDa (p12) subunit. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=3; Name=A; Synonyms=10-A; IsoId=Q92851-1; Sequence=Displayed; Name=B; Synonyms=10-B; IsoId=Q92851-2; Sequence=VSP_000819, VSP_000820; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=C; Synonyms=10-C; IsoId=Q92851-3; Sequence=VSP_000821, VSP_000822; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; TISSUE SPECIFICITY: Detectable in most tissues. Lowest expression is seen in brain, kidney, prostate, testis and colon. PTM: Cleavage by granzyme B and autocatalytic activity generate the two active subunits. DISEASE: Defects in CASP10 are the cause of type II autoimmune lymphoproliferative syndrome (ALPS2) [MIM:603909]. ALPS2 is characterized by abnormal lymphocyte and dendritic cell homeostasis and immune regulatory defects. SIMILARITY: Belongs to the peptidase C14 family. SIMILARITY: Contains 2 death effector (DED) domains. UniProt Q92851 1 1 FASL:FAS Receptor Trimer:FADD:pro-Caspase-10 [plasma membrane] FASL:FAS Receptor Trimer:FADD:pro-Caspase-10 1 1 Reactome 141310 http://www.reactome.org 11717445 Pubmed 2001 Caspase-10 is an initiator caspase in death receptor signaling Wang, J Chun, HJ Wong, W Spencer, DM Lenardo, MJ Proc Natl Acad Sci U S A 98:13884-8 12198154 Pubmed 2002 Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8 Sprick, MR Rieser, E Stahl, H Grosse-Wilde, A Weigand, MA Walczak, H EMBO J 21:4520-30 Reactome 75157 http://www.reactome.org 7538907 Pubmed 1995 FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis Chinnaiyan, AM O'Rourke, K Tewari, M Dixit, VM Cell 81:505-12 1713127 Pubmed 1991 The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis Itoh, N Yonehara, S Ishii, A Yonehara, M Mizushima, S Sameshima, M Hase, A Seto, Y Nagata, S Cell 66:233-43 11048727 Pubmed 2000 The biochemistry of apoptosis. Hengartner, MO Nature 407:770-6 2469768 Pubmed 1989 A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor Yonehara, S Ishii, A Yonehara, M J Exp Med 169:1747-56 TNF signaling TNF signaling The Tumor Necrosis Factor alpha (TNF-alpha) mediated apoptosis pathway has been implicated in the pathogenesis of a number of diseases including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The TNF signaling network provides extensive cross talk between the apoptotic pathway, and the other NF-B, and JNK pathways that also emanate from TNF-R. TNF Binds TNF-R1 TNF Binds TNF-R1 At the beginning of this reaction, 1 molecule of 'TNF-RI', and 1 molecule of 'TNF-alpha' are present. At the end of this reaction, 1 molecule of 'TNF-alpha:TNF-R1 complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 UniProt:P19438 Tumor necrosis factor receptor superfamily member 1A precursor (p60) (TNF-R1) (TNF-RI) (p55) (CD120a) [Contains: Tumor necrosis factor binding protein 1 (TBPI)] TNFRSF1A TNFR1 TNFAR FUNCTION: Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adaptor molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate- specific cysteine proteases) mediating apoptosis. Contributes to the induction of noncytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase. SUBUNIT: Binding of TNF to the extracellular domain leads to homotrimerization. The aggregated death domains provide a novel molecular interface that interacts specifically with the death domain of TRADD. Various TRADD-interacting proteins such as TRAFS, RIP and possibly FADD, are recruited to the complex by their association with TRADD. This complex activates at least two distinct signaling cascades, apoptosis and NF-kappa-B signaling. Binds BAG4. Constitutively associated with TRPC4AP (By similarity). SUBCELLULAR LOCATION: Type I membrane protein and secreted. DOMAIN: The domain that induces A-SMASE is probably identical to the death domain. The N-SMASE activation domain (NSD) is both necessary and sufficient for activation of N-SMASE. DOMAIN: Both the cytoplasmic membrane-proximal region and the C- terminal region containing the death domain are involved in the interaction with TRPC4AP (By similarity). PTM: The soluble form is produced from the membrane form by proteolytic processing. DISEASE: Defects in TNFRSF1A are a cause of autosomal dominant familial hibernian fever (FHF) [MIM:142680]; also known as tumour necrosis factor receptor-associated periodic syndrome (TRAPS). FHF is a disease characterized by recurrent fever, abdominal pain, localized tender skin lesions and myalgia. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 4 TNFR-Cys repeats. DATABASE: NAME=PROW; NOTE=CD guide CD120a entry; WWW="http://www.ncbi.nlm.nih.gov/prow/cd/cd120a.htm". UniProt P19438 1 UniProt:P01375 Tumor necrosis factor precursor (TNF-alpha) (Tumor necrosis factor ligand superfamily member 2) (TNF-a) (Cachectin) TNF TNFA TNFSF2 FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin 1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. SUBUNIT: Homotrimer. SUBCELLULAR LOCATION: Type II membrane protein. Also exists as an extracellular soluble form. PTM: The soluble form derives from the membrane form by proteolytic processing. PTM: The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form ocurrs by binding to soluble TNFRSF1A/TNFR1. DISEASE: Cachexia accompanies a variety of diseases, including cancer and infection, and is characterized by general ill health and malnutrition. SIMILARITY: Belongs to the tumor necrosis factor family. CAUTION: Ref.8 sequence differs from that shown due to erroneous gene model prediction. CAUTION: Ref.15 sequence differs from that shown due to frameshifts in positions 91 and 157. UniProt P01375 1 TNF-alpha:TNF-R1 complex [plasma membrane] TNF-alpha:TNF-R1 complex 1 1 Reactome 83660 http://www.reactome.org 2848815 Pubmed 1988 Human tumor necrosis factor-alpha receptor. Purification by immunoaffinity chromatography and initial characterization. Stauber, GB Aiyer, RA Aggarwal, BB J Biol Chem 263:19098-104 TNF:TNF-R1 binds TRADD, TRAF2 and RIP Complex TNF:TNF-R1 binds TRADD, TRAF2 and RIP Complex Once the TNF-aplha:TNF-R1:TRADD complex is formed the two TNF-alpha mediated pathways are possible. The variable is the recruitment of FADD to the larger complex formed by the TNF-aplha:TNF-R1 platform via the interaction of the Death Domains. The steps leading to the Jun, NF kappaB, or apoptotic pathways are rife with modulation. 1 1 UniProt:Q15628 Tumor necrosis factor receptor type 1 associated DEATH domain protein (TNFR1-associated DEATH domain protein) (TNFRSF1A-associated via death domain) TRADD FUNCTION: Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B. SUBUNIT: Heterodimer with TNFRSF1A/TNFR1. Binds to TRAF2. Interacts with TRAF1, FADD, RIPK1 and TRPC4AP (By similarity). TISSUE SPECIFICITY: Found in all examined tissues. DOMAIN: Requires the intact DEATH domain to associate with TNFRSF1A/TNFR1. SIMILARITY: Contains 1 death domain. UniProt Q15628 1 UniProt:Q12933-1 TNF receptor associated factor 2 (Tumor necrosis factor type 2 receptor associated protein 3) TRAP3 TRAF2 FUNCTION: Adapter protein and signal transducer that links members of the tumor necrosis factor receptor family to different signaling pathways by association with the receptor cytoplasmic domain and kinases. Association to the receptor is also mediated by the interaction with TRADD. Mediates activation of NF-kappa-B and JNK and is involved in apoptosis. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. Seems to be involved in IL-15 signaling. SUBUNIT: Homotrimer (Probable). Heteromer with TRAF1. Binds to TNFRSF1B/TNFR2, TNFRSF4 and TNFRSF5/CD40. Associates with TNFRSF7/CD27, TNFRSF8/CD30, TNFRSF9/CD137, TNFRSF11A/RANK, TNFRSF13B/TACI. TNFRSF14, TNFRSF16/NGFR, TNFRSF17/BCMA, TNFRSF18/AITR, TNFRSF19/TROY, TNFRSF19L/RELT, XEDAR, EDAR, Epstein-Barr virus BNFL1/LMP-1, IL15RA, TANK/ITRAF, RIPK2, TNIK, MAP3K14, MAP3K5, MAP3K1, MAP4K2, CDK9, CSK, and TRAF-interacting protein TRAIP and TRAF and TNF receptor associated protein TTRAP. Interacts with TNFAIP3 and TRPC4AP (By similarity). Binds to TRADD. Interacts with BIRC2 and BIRC3 N-terminus. Interacts with CYLD. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q12933-1; Sequence=Displayed; Name=2; IsoId=Q12933-2; Sequence=VSP_007401; Note=No experimental confirmation available; DOMAIN: The coiled coil domain mediates homo- and hetero- oligomerization. DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains. PTM: Ubiquitinated; mediated by SIAH2 and leading to its subsequent proteasomal degradation. Not ubiquitinated by SIAH1. SIMILARITY: Contains 1 MATH domain. SIMILARITY: Contains 1 RING-type zinc finger. SIMILARITY: Contains 2 TRAF-type zinc fingers. UniProt Q12933 1 UniProt:Q13546 Receptor-interacting serine/threonine-protein kinase 2 (EC 2.7.1.37) (Serine/threonine-protein kinase RIP) (Cell death protein RIP) (Receptor interacting protein) RIP RIPK1 FUNCTION: Promotes apoptosis and activation of NF-kappa-B. Required for TNFRSF1A mediated activation of NF-kappa-B. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBUNIT: Binds to the death domain of TNFRSF6 and TRADD. Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RIPK3, UBCE7IP1, EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. SUBCELLULAR LOCATION: Cytoplasmic. PTM: Proteolytically cleaved by caspase-8 during TNF-induced apoptosis. Cleavage abolishes NF-kappa-B activation and enhances pro-apototic signaling through the TRADD-FADD interaction. PTM: Autophosphorylated on serine and threonine residues. SIMILARITY: Belongs to the Ser/Thr protein kinase family. SIMILARITY: Contains 1 death domain. UniProt Q13546 1 TNF-alpha:TNF-R1:TRAPP:RIP1:TRAF2 Complex [plasma membrane] TNF-alpha:TNF-R1:TRAPP:RIP1:TRAF2 Complex 1 1 1 1 Reactome 83656 http://www.reactome.org 7758105 Pubmed 1995 The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation Hsu, H Xiong, J Goeddel, DV Cell 81:495-504 TRADD:TRAF2:RIP1 complex dissociates from the TNF-alpha:TNF-R1 complex. TRADD:TRAF2:RIP1 complex dissociates from the TNF-alpha:TNF-R1 complex. Once formed the TRADD:TRAF2:RIP1 complex may dissociate from the TNF:TNF-R1 platform and become cytosolic. If this complex recruits FADD then the cell will be pushed along the apoptotic pathway. 1 1 1 TRAF2:TRADD:RIP1 Complex [cytosol] TRAF2:TRADD:RIP1 Complex 1 1 1 Reactome 83582 http://www.reactome.org 12887920 Pubmed 2003 Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes Micheau, O Tschopp, J Cell 114:181-90 TRADD:TRAF2:RIP1 complex binds FADD TRADD:TRAF2:RIP1 complex binds FADD Once formed the TRADD:TRAF2:RIP1 complex may dissociate from the TNF:TNF-R1 platform and become cytosolic. If this complex recruits FADD then the cell will be pushed along the apoptotic pathway. 1 1 1 TRAF2:TRADD:RIP1:FADD [cytosol] TRAF2:TRADD:RIP1:FADD 1 1 Reactome 140978 http://www.reactome.org TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8 TRADD:TRAF2:RIP1:FADD complex binds Pro-Caspase 8 At the beginning of this reaction, 1 molecule of 'TRAF2:TRADD:RIP1:FADD', and 1 molecule of 'Caspase-8 precursor ' are present. At the end of this reaction, 1 molecule of 'TRADD:TRAF2:RIP1:FADD:Capase-8 Complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 TRADD:TRAF2:RIP1:FADD:Capase-8 Complex [cytosol] TRADD:TRAF2:RIP1:FADD:Capase-8 Complex 1 1 Reactome 75240 http://www.reactome.org Reactome 75893 http://www.reactome.org 12040173 Pubmed 2002 TNF-R1 signaling: a beautiful pathway Chen, G Goeddel, DV Science 296:1634-5 TRAIL signaling TRAIL signaling Tumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work through protein interactions mediated by the intracellular death domain (DD), encoded within the cytoplasmic domain of the receptor. TRAIL selectively induces apoptosis through its interaction with the Fas-associated death domain protein (FADD). TRAIL Binds TRAIL-Receptor2 TRAIL Binds TRAIL-Receptor2 At the beginning of this reaction, 1 molecule of 'TRAIL receptor-2', and 1 molecule of 'TRAIL' are present. At the end of this reaction, 1 molecule of 'TRAIL receptor-2:TRAIL complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 UniProt:P50591 Tumor necrosis factor ligand superfamily member 10 (TNF-related apoptosis inducing ligand) (TRAIL protein) (Apo-2 ligand) (Apo-2L) APO2L TNFSF10 TRAIL FUNCTION: Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG. Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis. COFACTOR: Binds 1 zinc ion and one anionic solvent molecule per trimer. SUBUNIT: Homotrimer. SUBCELLULAR LOCATION: Type II membrane protein (Potential). TISSUE SPECIFICITY: Widespread; most predominant in spleen, lung and prostate. SIMILARITY: Belongs to the tumor necrosis factor family. UniProt P50591 1 UniProt:O14763-1 Tumor necrosis factor receptor superfamily member 10B precursor (Death receptor 5) (TNF-related apoptosis-inducing ligand receptor 2) (TRAIL receptor-2) (TRAIL-R2) KILLER ZTNFR9 TRICK2 DR5 TRAILR2 TNFRSF10B FUNCTION: Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adaptor molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF- kappa-B. SUBUNIT: Homotrimer. Can interact with TRADD and RIP. SUBCELLULAR LOCATION: Type I membrane protein. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=Long; Synonyms=TRICK2B; IsoId=O14763-1; Sequence=Displayed; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=Short; Synonyms=TRICK2A; IsoId=O14763-2; Sequence=VSP_006490; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; TISSUE SPECIFICITY: Widely expressed in adult and fetal tissues; very highly expressed in tumor cell lines such as HeLa S3, K562, HL-60, SW480, A549 and G361; highly expressed in heart, peripheral blood lymphocytes, liver, pancreas, spleen, thymus, prostate, ovary, uterus, placenta, testis, esophagus, stomach and throughout the intestinal tract; not detectable in brain. INDUCTION: TNFRSF10B is regulated by the tumor suppressor p53. DISEASE: Defects in TNFRSF10B may be a cause of squamous cell carcinoma of the head and neck (HNSCC) [MIM:601400]. SIMILARITY: Contains 1 death domain. SIMILARITY: Contains 3 TNFR-Cys repeats. UniProt O14763 1 TRAIL receptor-2:TRAIL complex [plasma membrane] TRAIL receptor-2:TRAIL complex 1 1 Reactome 75238 http://www.reactome.org 8777713 Pubmed 1995 Identification and characterization of a new member of the TNF family that induces apoptosis Wiley, SR Schooley, K Smolak, PJ Din, WS Huang, CP Nicholl, JK Sutherland, GR Smith, TD Rauch, C Smith, CA Immunity 3:673-82 Trimerization of TRAIL: TRAIL receptor-2 complex Trimerization of TRAIL: TRAIL receptor-2 complex At the beginning of this reaction, 3 molecules of 'TRAIL receptor-2:TRAIL complex' is present. At the end of this reaction, 1 molecule of 'TRAIL receptor-2:TRAIL Trimer' is present.<br><br> This reaction takes place in the 'cell'.<br> 3 1 TRAIL receptor-2:TRAIL Trimer [plasma membrane] TRAIL receptor-2:TRAIL Trimer 3 Reactome 141139 http://www.reactome.org 10894160 Pubmed 2000 FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2 Sprick, MR Weigand, MA Rieser, E Rauch, CT Juo, P Blenis, J Krammer, PH Walczak, H Immunity 12:599-609 TRAIL:TRAIL receptor-2 Trimer Binds FADD TRAIL:TRAIL receptor-2 Trimer Binds FADD At the beginning of this reaction, 1 molecule of 'FADD', and 1 molecule of 'TRAIL receptor-2:TRAIL Trimer' are present. At the end of this reaction, 1 molecule of 'TRAIL:TRAIL receptor-2:FADD complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 TRAIL:TRAIL receptor-2:FADD complex [plasma membrane] TRAIL:TRAIL receptor-2:FADD complex 1 1 Reactome 75187 http://www.reactome.org TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-8 TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-8 At the beginning of this reaction, 1 molecule of 'Caspase-8 precursor ', and 1 molecule of 'TRAIL:TRAIL receptor-2:FADD complex' are present. At the end of this reaction, 1 molecule of 'TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex [plasma membrane] TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex 1 1 Reactome 75146 http://www.reactome.org TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-10 TRAIL:TRAIL-Receptor2 Trimer:FADD complex binds Caspase-10 At the beginning of this reaction, 1 molecule of 'Caspase-10 precursor ', and 1 molecule of 'TRAIL:TRAIL receptor-2:FADD complex' are present. At the end of this reaction, 1 molecule of 'TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-10 precursor complex' is present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-10 precursor complex [plasma membrane] TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-10 precursor complex 1 1 Reactome 141316 http://www.reactome.org Reactome 75158 http://www.reactome.org 14634624 Pubmed 2003 TRAIL and apoptosis induction by TNF-family death receptors Wang, S el-Deiry, WS Oncogene 22:8628-33 Reactome 73887 http://www.reactome.org Caspase-8 is formed from procaspase-8 Caspase-8 is formed from procaspase-8 Activation of Pro-Caspase 8 Activation of Pro-Caspase 8 FAS Mediated Activation of Pro-caspase 8 FAS Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'FASL:FAS Receptor Trimer:FADD:pro-Caspase-8 DISC' is present. At the end of this reaction, 1 molecule of 'p10 subunit of Caspase 8', 1 molecule of 'p18 subunit of Caspase 8', and 1 molecule of 'FASL:FAS Receptor Trimer:FADD complex' are present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 1 Reactome 73945 http://www.reactome.org 9721089 Pubmed 1998 Death receptors: signaling and modulation Ashkenazi, A Dixit, VM Science 281:1305-8 TRAIL Mediated Activation of Pro-caspase 8 TRAIL Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'TRAIL:TRAIL receptor-2 Trimer:FADD:Caspase-8 precursor complex' is present. At the end of this reaction, 1 molecule of 'p10 subunit of Caspase 8', 1 molecule of 'TRAIL:TRAIL receptor-2:FADD complex', and 1 molecule of 'p18 subunit of Caspase 8' are present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 1 Reactome 141156 http://www.reactome.org TNF Mediated Activation of Pro-caspase 8 TNF Mediated Activation of Pro-caspase 8 At the beginning of this reaction, 1 molecule of 'TRADD:TRAF2:RIP1:FADD:Capase-8 Complex' is present. At the end of this reaction, 1 molecule of 'TRAF2:TRADD:RIP1:FADD', 1 molecule of 'p10 subunit of Caspase 8', and 1 molecule of 'p18 subunit of Caspase 8' are present.<br><br> This reaction takes place in the 'cell'.<br> 1 1 1 1 Reactome 141159 http://www.reactome.org Reactome 69416 http://www.reactome.org GO 0006919 GO biological process Formation of Caspase-8 dimer Formation of Caspase-8 dimer At the beginning of this reaction, 1 molecule of 'p10 subunit of Caspase 8', and 1 molecule of 'p18 subunit of Caspase 8' are present. At the end of this reaction, 1 molecule of 'Caspase-8 dimer' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 1 Caspase-8 dimer [cytosol] Caspase-8 dimer 1 1 Reactome 139952 http://www.reactome.org Reactome 140534 http://www.reactome.org 14644197 Pubmed 2003 Mechanisms of caspase activation Boatright, KM Salvesen, GS Curr Opin Cell Biol 15:725-31 GO 0008633 GO biological process Reactome 109607 http://www.reactome.org Activation, myristolyation of BID and translocation to mitochondria Activation, myristolyation of BID and translocation to mitochondria Activation of BID and translocation to mitochondria BID may promote cell death by activating BAX and BAK while inactivating anti-apoptotic proteins. The engagement of cell surface receptors activates the caspase-8, a heterodimer, that cleaves BID in its amino terminal region. This particular event may act as a link between Extrinsic (caspase 8/10 dependent) and Intrinsic (Bcl-2 inhibitable) pathways although some evidences from mouse genetic experiments suggest the contrary. It has been suggested that the death signals from the extrinsic or death receptor pathway may get amplified by the mechanisms of intrinsic pathway and that this functional loop may be enabled by the molecules like tBID (truncated BID).<BR> Cleavage of BID to tBID can also be achieved by Granzyme B. The truncated protein is myristoylated and translocates to mitochondria. Caspase-8 activates BID by cleavage Caspase-8 activates BID by cleavage 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. 1 UniProt:P55957 BH3 interacting domain death agonist (BID) BID FUNCTION: Induces ICE-like proteases and apoptosis. Counters the protective effect of Bcl-2 (By similarity). SUBUNIT: Forms heterodimers either with the pro-apoptotic protein BAX or the anti-apoptotic protein Bcl-2 (By similarity). SUBCELLULAR LOCATION: Predominantly cytoplasmic (By similarity). DOMAIN: Intact BH3 domain is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. UniProt P55957 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION GO 0030693 GO molecular function Reactome 139898 http://www.reactome.org 12804595 Pubmed 2003 Caspase 8-mediated cleavage of the pro-apoptotic BCL-2 family member BID in p53-dependent apoptosis Fischer, B Coelho, D Dufour, P Bergerat, JP Denis, JM Gueulette, J Bischoff, P Biochem Biophys Res Commun 306:516-22 9873064 Pubmed 1999 Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death Gross, A Yin, XM Wang, K Wei, MC Jockel, J Milliman, C Erdjument-Bromage, H Tempst, P Korsmeyer, SJ J Biol Chem 274:1156-63 3.4.21.79 Granzyme-B activates BID by cleavage Granzyme-B activates BID by cleavage At the beginning of this reaction, 1 molecule of 'BID' is present. At the end of this reaction, 1 molecule of 'tBID-p15' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'granzyme B activity' of 'Granzyme B'.<br> 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION UniProt:P10144 Granzyme B precursor (EC 3.4.21.79) (T-cell serine protease 1-3E) (Cytotoxic T-lymphocyte proteinase 2) (Lymphocyte protease) (SECT) (Granzyme 2) (Cathepsin G-like 1) (CTSGL1) (CTLA-1) (Fragmentin 2) (Human lymphocyte protein) (HLP) (C11) GZMB CGL1 GRB CSPB CTLA1 FUNCTION: This enzyme is necessary for target cell lysis in cell- mediated immune responses. It cleaves after Asp. Seems to be linked to an activation cascade of caspases (aspartate-specific cysteine proteases) responsible for apoptosis execution. Cleaves caspase-3, -7, -9 and 10 to give rise to active enzymes mediating apoptosis. CATALYTIC ACTIVITY: Preferential cleavage: Asp-|-Xaa >> Asn-|-Xaa > Met-|-Xaa, Ser-|-Xaa. SUBCELLULAR LOCATION: Cytoplasmic granules of cytolytic T- lymphocytes and natural killer cells. INDUCTION: By staphylococcal enterotoxin A (SEA) in peripheral blood leukocytes. SIMILARITY: Belongs to the peptidase S1 family. Granzyme subfamily. UniProt P10144 GO 0004278 GO molecular function Reactome 139893 http://www.reactome.org 11114298 Pubmed 2001 Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition Alimonti, JB Shi, L Baijal, PK Greenberg, AH J Biol Chem 276:6974-82 Myristoylation of tBID by NMT1 Myristoylation of tBID by NMT1 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. 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION UniProt:P30419-1 Glycylpeptide N-tetradecanoyltransferase 1 (EC 2.3.1.97) (Peptide N- myristoyltransferase 1) (Myristoyl-CoA:protein N-myristoyltransferase 1) (NMT 1) (Type I N-myristoyltransferase) NMT NMT1 FUNCTION: Adds a myristoyl group to the N-terminal glycine residue of certain cellular and viral proteins. CATALYTIC ACTIVITY: Tetradecanoyl-CoA + glycyl-peptide = CoA + N- tetradecanoylglycyl-peptide. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=Long; IsoId=P30419-1; Sequence=Displayed; Name=Short; IsoId=P30419-2; Sequence=VSP_003570; TISSUE SPECIFICITY: Heart, gut, kidney, liver and placenta. SIMILARITY: Belongs to the NMT family. UniProt P30419 GO 0019107 GO molecular function Reactome 141367 http://www.reactome.org 11099414 Pubmed 2000 Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis Zha, J Weiler, S Oh, KJ Wei, MC Korsmeyer, SJ Science 290:1761-5 Translocation of tBID to mitochondria Translocation of tBID to mitochondria At the beginning of this reaction, 1 molecule of 'tBID' is present. At the end of this reaction, 1 molecule of 'tBID' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 mitochondrial outer membrane GO 0005741 Reactome 139920 http://www.reactome.org Reactome 75108 http://www.reactome.org 14634621 Pubmed 2003 The Bcl-2 family: roles in cell survival and oncogenesis. Cory, S Huang, DC Adams, JM Oncogene 22:8590-607 9727492 Pubmed 1998 Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis Li, H Zhu, H Xu, CJ Yuan, J Cell 94:491-501 Intrinsic Pathway for Apoptosis Intrinsic Pathway for Apoptosis 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: <p> 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. Activation of BH3-only proteins Activation of BH3-only proteins The BH3-only members act as sentinels that selectively trigger apoptosis in response to developmental cues or stress-signals like DNA damages. Widely expressed mammalian BH3-only proteins are thought to act by binding to and neutralizing their pro-survival counterparts. Activation of BH3-only proteins directly or indirectly results in the activation of proapoptotic BAX and BAK to trigger cell death. Anti-apoptotic BCL-2 or BCL-XL may bind and sequester BH3-only molecules to prevent BAX, BAK activation. The individual BH3-only members are held in check by various mechanisms with in the cells. They are recruited for death duties in response to death cues by diverse activation processes.The mechanisms involved in activation and release of BH3-only proteins for apoptosis will be discussed in this section. <p>The following figure has been reproduced here with the kind permission from the authors. Activation of BAD and translocation to mitochondria Activation of BAD and translocation to mitochondria The switching on/off of its phosphorylation by growth/survival factors regulates BAD activity. BAD remains sequestered by 14-3-3 scaffold proteins after phosphorylation by Akt1. Calcineurin activates BAD by dephosphorylation. Akt1 phosphorylates BAD protein Akt1 phosphorylates BAD protein At the beginning of this reaction, 1 molecule of 'BAD protein' is present. At the end of this reaction, 1 molecule of 'Phospho-BAD' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'kinase activity' of 'AKT1'.<br> 1 UniProt:Q92934 Bcl2-antagonist of cell death (BAD) (Bcl-2 binding component 6) (Bcl- XL/Bcl-2 associated death promoter) (Bcl-2-like 8 protein) BCL2L8 BAD BBC6 FUNCTION: Promotes cell death. Successfully competes for the binding to Bcl-X(L), Bcl-2 and Bcl-W, thereby affecting the level of heterodimerization of these proteins with BAX. Can reverse the death repressor activity of Bcl-X(L), but not that of Bcl-2 (By similarity). Appears to act as a link between growth factor receptor signaling and the apoptotic pathways. SUBUNIT: Forms heterodimers with the anti-apoptotic proteins, Bcl- X(L), Bcl-2 and Bcl-W. Also binds protein S100A10 (By similarity). The Ser-75/Ser-99 phosphorylated form binds 14-3-3 proteins (By similarity). SUBCELLULAR LOCATION: Outer mitochondrial membrane. Upon phosphorylation, locates to the cytoplasm. TISSUE SPECIFICITY: Expressed in a wide variety of tissues. DOMAIN: Intact BH3 domain is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family. PTM: Phosphorylated on Ser-75 in response to survival stimuli. Subsequent phosphorylation on Ser-99 promotes heterodimerization with 14-3-3 proteins. This interaction then facilitates the phosphorylation at Ser-118, a site within the BH3 domain, leading to the release of Bcl-X(L) and the promotion of cell survival. Ser-99 is the major site of AKT/PKB phosphorylation, Ser-118 the major site of protein kinase A (CAPK) phosphorylation (By similarity). SIMILARITY: Belongs to the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. CAUTION: Ref.1 sequence differs from that shown due to frameshifts in positions 64 and 91. UniProt Q92934 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION UniProt:P31749 RAC-alpha serine/threonine-protein kinase (EC 2.7.1.37) (RAC-PK-alpha) (Protein kinase B) (PKB) (C-AKT) PKB RAC AKT1 FUNCTION: General protein kinase capable of phosphorylating several known proteins. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. SUBCELLULAR LOCATION: Cytoplasmic and nuclear after activation by integrin-linked protein kinase 1 (ILK1). TISSUE SPECIFICITY: In all human cell types so far analyzed. DOMAIN: Binding of the PH domain to the phosphatidylinositol 3- kinase alpha (PI(3)K) results in its targeting to the plasma membrane. PTM: Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. SIMILARITY: Belongs to the Ser/Thr protein kinase family. RAC subfamily. SIMILARITY: Contains 1 PH domain. UniProt P31749 GO 0016301 GO molecular function Reactome 139903 http://www.reactome.org 15183529 Pubmed 2004 Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 15183529 Khor, TO Gul, YA Ithnin, H Seow, HF Cancer Lett 210:139-50 Sequestration of BAD protein by 14-3-3 Sequestration of BAD protein by 14-3-3 At the beginning of this reaction, 1 molecule of '143B protein', and 1 molecule of 'Phospho-BAD' are present. At the end of this reaction, 1 molecule of '143B:phospo-BAD complex' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 UniProt:P31946 14-3-3 protein beta/alpha (Protein kinase C inhibitor protein-1) (KCIP-1) (Protein 1054) YWHAB FUNCTION: Activates tyrosine and tryptophan hydroxylases in the presence of Ca(2+)/calmodulin-dependent protein kinase II, and strongly activates protein kinase C. Is probably a multifunctional regulator of the cell signaling processes mediated by both kinases. SUBUNIT: Homodimer. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative initiation; Comment=2 isoforms, Long (shown here) and Short, are produced by alternative initiation; TISSUE SPECIFICITY: 14-3-3 proteins are localized in neurons, and are axonally transported to the nerve terminals. They may be also present, at lower levels, in various other eukaryotic tissues. PTM: Isoform alpha differs from isoform beta in being phosphorylated (By similarity). SIMILARITY: Belongs to the 14-3-3 family. UniProt P31946 1 1 143B:phospo-BAD complex [cytosol] 143B:phospo-BAD complex 1 1 Reactome 139899 http://www.reactome.org 12657644 Pubmed 2003 Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis Won, J Kim, DY La, M Kim, D Meadows, GG Joe, CO J Biol Chem 278:19347-51 Activation of BAD by calcineurin Activation of BAD by calcineurin At the beginning of this reaction, 1 molecule of '143B:phospo-BAD complex' is present. At the end of this reaction, 1 molecule of 'BAD protein', and 1 molecule of '143B protein' are present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'calcium-dependent protein serine/threonine phosphatase regulator activity' of 'Calcineurin B complex'.<br> 1 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Calcineurin B complex [cytosol] Calcineurin B complex 1 UniProt:P48454 Serine/threonine protein phosphatase 2B catalytic subunit, gamma isoform (EC 3.1.3.16) (Calmodulin-dependent calcineurin A subunit, gamma isoform) (Calcineurin, testis-specific catalytic subunit) (CAM- PRP catalytic subunit) CALNA3 PPP3CC CNA3 FUNCTION: Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin. CATALYTIC ACTIVITY: A phosphoprotein + H(2)O = a protein + phosphate. COFACTOR: Binds 1 iron(III) ion and 1 zinc ion per subunit (By similarity). SUBUNIT: Composed of two components (A and B), the A component is the catalytic subunit and the B component confers calcium sensitivity. TISSUE SPECIFICITY: Testis. SIMILARITY: Belongs to the PPP phosphatase family. PP-2B subfamily. UniProt P48454 1 UniProt:P63098 Calcineurin B subunit isoform 1 (Protein phosphatase 2B regulatory subunit 1) (Protein phosphatase 3 regulatory subunit B alpha isoform 1) CNA2 CNB PPP3R1 FUNCTION: Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity. SUBUNIT: Composed of a catalytic subunit (A) and a regulatory subunit (B). MISCELLANEOUS: This protein has four functional calcium-binding sites. SIMILARITY: Contains 4 EF-hand calcium-binding domains. UniProt P63098 GO 0008597 GO molecular function Reactome 139906 http://www.reactome.org 10195903 Pubmed 1999 Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Wang, HG Pathan, N Ethell, IM Krajewski, S Yamaguchi, Y Shibasaki, F McKeon, F Bobo, T Franke, TF Reed, JC Science 284:339-43 Translocation of activated BAD protein to mitochondria Translocation of activated BAD protein to mitochondria At the beginning of this reaction, 1 molecule of 'BAD protein' is present. At the end of this reaction, 1 molecule of 'BAD protein' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 Reactome 139905 http://www.reactome.org GO 0001844 GO biological process BAD displaces tBID from BCL-2 sequestration BAD displaces tBID from BCL-2 sequestration Short peptides representing BAD and BIX were found to bind BCL-2 displacing BID-like BH3 domains that initiate mitochondrial dysfunction. 1 1 tBID:BCL-2 [mitochondrial outer membrane] tBID:BCL-2 1 1 UniProt:P10415-1 Apoptosis regulator Bcl-2 BCL2 FUNCTION: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1). SUBUNIT: Forms homodimers, and heterodimers with BAX, BAD, BAK and Bcl-X(L). Heterodimerization with BAX requires intact BH1 and BH2 domains, and is necessary for anti-apoptotic activity (By similarity). Also interacts with APAF-1, RAF-1 and TP53BP2. SUBCELLULAR LOCATION: Outer mitochondrial membrane, intracellular membrane of the nuclear envelope and the endoplasmic reticulum. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=Alpha; IsoId=P10415-1; Sequence=Displayed; Name=Beta; IsoId=P10415-2; Sequence=VSP_000512; TISSUE SPECIFICITY: Expressed in a variety of tissues. DOMAIN: The BH4 domain is required for anti-apoptotic activity and for interaction with RAF-1. PTM: Phosphorylation/dephosphorylation on Ser-70 regulates Bcl2 anti-apoptotic activity. Growth factor-stimulated phosphorylation on Ser-70 by PKC is required for the anti-apoptosis activity and occurs during the G2/M phase of the cell cycle. In the absence of growth factors, Bcl2 appears to be phosphorylated by other protein kinases such as ERKs and stress-activated kinases. Dephosphorylated by protein phosphatase 2A (PP2A) (By similarity). PTM: Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 domain, has pro-apoptotic activity, causes the release of cytochrome c into the cytosol promoting further caspase activity. DISEASE: Involved in follicular lymphoma (FL) (also known as type II chronic lymphatic leukemia) by a chromosomal translocation t(14;18)(q32;q21) which involves BCL2 and immunoglobulin gene regions. BCL2 mutations found in non-Hodgin's lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. SIMILARITY: Belongs to the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 1 (BH1) domain. SIMILARITY: Contains 1 Bcl-2 homology 2 (BH2) domain. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. SIMILARITY: Contains 1 Bcl-2 homology 4 (BH4) domain. DATABASE: NAME=Atlas Genet. Cytogenet. Oncol. Haematol.; WWW="http://www.infobiogen.fr/services/chromcancer/Genes/BCL2ID49.html". UniProt P10415 1 1 BAD:BCL-2 [mitochondrial outer membrane] BAD:BCL-2 1 1 Reactome 139897 http://www.reactome.org 12242151 Pubmed 2002 Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics Letai, A Bassik, MC Walensky, LD Sorcinelli, MD Weiler, S Korsmeyer, SJ Cancer Cell 2:183-92 Reactome 111447 http://www.reactome.org 15231831 Pubmed 2004 BAD Is a Pro-survival Factor Prior to Activation of Its Pro-apoptotic Function. Seo, SY Chen, YB Ivanovska, I Ranger, AM Hong, SJ Dawson, VL Korsmeyer, SJ Bellows, DS Fannjiang, Y Hardwick, JM J Biol Chem 279:42240-9 12209154 Pubmed 2002 The Bcl2 family: regulators of the cellular life-or-death switch Cory, S Adams, JM Nat Rev Cancer 2:647-56 Activation of NOXA and translocation to mitochondria Activation of NOXA and translocation to mitochondria Transactivation of NOXA by p53 Transactivation of NOXA by p53 At the end of this reaction, 1 molecule of 'NOXA protein' is present. <br><br><br> 1 UniProt:Q13794 Phorbol-12-myristate-13-acetate-induced protein 1 (PMA-induced protein 1) (Immediate-early-response protein APR) PMAIP1 TISSUE SPECIFICITY: Highly expressed in adult T-cell leukemia cell line. UniProt Q13794 Reactome 140214 http://www.reactome.org 15126337 Pubmed 2004 Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53 Li, CQ Robles, AI Hanigan, CL Hofseth, LJ Trudel, LJ Harris, CC Wogan, GN Cancer Res 64:3022-9 Transactivation of NOXA by E2F1 Transactivation of NOXA by E2F1 At the end of this reaction, 1 molecule of 'NOXA protein' is present. <br><br><br> 1 Reactome 140217 http://www.reactome.org 14684737 Pubmed 2004 Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis Hershko, T Ginsberg, D J Biol Chem 279:8627-34 Translocation of NOXA to mitochondria Translocation of NOXA to 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. 1 1 Reactome 140216 http://www.reactome.org 10807576 Pubmed 2000 Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis Oda, E Ohki, R Murasawa, H Nemoto, J Shibue, T Yamashita, T Tokino, T Taniguchi, T Tanaka, N Science 288:1053-8 Reactome 111448 http://www.reactome.org Activation of PUMA and translocation to mitochondria Activation of PUMA and translocation to mitochondria Transactivation of PUMA by p53 Transactivation of PUMA by p53 At the end of this reaction, 1 molecule of 'PUMA protein' is present. <br><br><br> 1 UniProt:Q9BXH1 PUMA protein PUMA protein UniProt Q9BXH1 Reactome 139913 http://www.reactome.org 11463392 Pubmed 2001 PUMA, a novel proapoptotic gene, is induced by p53 Nakano, K Vousden, KH Mol Cell 7:683-94 Transactivation of PUMA by E2F1 Transactivation of PUMA by E2F1 At the end of this reaction, 1 molecule of 'PUMA protein' is present. <br><br><br> 1 Reactome 140221 http://www.reactome.org Translocation of PUMA protein to mitochondria Translocation of PUMA protein to mitochondria 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. 1 1 Reactome 139914 http://www.reactome.org 11463391 Pubmed 2001 PUMA induces the rapid apoptosis of colorectal cancer cells Yu, J Zhang, L Hwang, PM Kinzler, KW Vogelstein, B Mol Cell 7:673-82 Reactome 139915 http://www.reactome.org Activation of BIM and translocation to mitochondria Activation of BIM and translocation to mitochondria BIM acts as a sentinel to check the integrity of the cytoskeleton. It exists as two variant proteins: BIM-EL and BIM-L. In healthy cells, these two isoforms are sequestered to the dynein motor complex on microtubules via the dynein light chain DLC1. JNK or MAPK8 releases BIM in response to UV irradiation by phosphorylation. Phosphorylation of DLC1 by MAPK 8 Phosphorylation of DLC1 by MAPK 8 At the beginning of this reaction, 1 molecule of 'BIM sequestered to dynein (DLC1)' is present. At the end of this reaction, 1 molecule of 'BIM', and 1 molecule of 'phospho-dynein(DLC1) on microtubules' are present.<br><br> This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'Mitogen-activated protein kinase 8 '.<br> 1 BIM sequestered to dynein (DLC1) [plasma membrane] BIM sequestered to dynein (DLC1) 1 UniProt:O43521-1 Bcl-2-like protein 11 (Bcl2 interacting mediator of cell death) BCL2L11 BIM FUNCTION: Induces apoptosis. Isoform BimL is more potent than isoform BimEL. SUBUNIT: Forms heterodimers with a number of antiapoptotic Bcl-2 proteins including Mcl-1, Bcl-2, Bcl-X(L), BFL-1, and BHRF1. Does not heterodimerize with proapoptotic proteins such as BAD, BOK, BAX or BAK (By similarity). SUBCELLULAR LOCATION: Associated with intracytoplasmic membranes (By similarity). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=BimEL; IsoId=O43521-1; Sequence=Displayed; Name=BimL; IsoId=O43521-2; Sequence=VSP_000535; DOMAIN: The BH3 domain is required for Bcl-2 binding and cytotoxicity. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. UniProt O43521 1 microtubules [plasma membrane] microtubules 1 UniProt:P63167 Dynein light chain 1, cytoplasmic (8 kDa dynein light chain) (DLC8) (Protein inhibitor of neuronal nitric oxide synthase) (PIN) DNCL1 DNCLC1 DLC1 HDLC1 FUNCTION: May be involved in some aspects of dynein-related intracellular transport and motility. May play a role in changing or maintaining the spatial distribution of cytoskeletal structures. FUNCTION: Binds and inhibits the catalytic activity of neuronal nitric oxide synthase. SUBUNIT: Consists of at least two heavy chains and a number of intermediate and light chains. SUBCELLULAR LOCATION: Cytoplasmic. TISSUE SPECIFICITY: Ubiquitous. SIMILARITY: Belongs to the dynein light chain family. UniProt P63167 1 phospho-dynein(DLC1) on microtubules [plasma membrane] phospho-dynein(DLC1) on microtubules 1 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION UniProt:P45983-1 Mitogen-activated protein kinase 8 (EC 2.7.1.37) (Stress-activated protein kinase JNK1) (c-Jun N-terminal kinase 1) (JNK-46) PRKM8 JNK1 MAPK8 FUNCTION: Responds to activation by environmental stress and pro- inflammatory cytokines by phosphorylating a number of transcription factors, primarily components of AP-1 such as c-Jun and ATF2 and thus regulates AP-1 transcriptional activity. In T- cells, JNK1 and JNK2 are required for polarized differentiation of T-helper cells into Th1 cells (By similarity). FUNCTION: JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta- 2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. COFACTOR: Magnesium. ENZYME REGULATION: Activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. Inhibited by dual specificity phosphatases, such as DUSP1. SUBUNIT: Binds to at least three scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2 and MAPK8IP3/JIP-3/JSAP1. These proteins also bind other components of the JNK signaling pathway (By similarity). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=4; Name=2; Synonyms=JNK1-alpha-2; IsoId=P45983-1; Sequence=Displayed; Name=1; Synonyms=JNK1-alpha-1; IsoId=P45983-2; Sequence=VSP_004833; Name=3; Synonyms=JNK1-beta-1; IsoId=P45983-3; Sequence=VSP_004831, VSP_004832, VSP_004833; Name=4; Synonyms=JNK1-beta-2; IsoId=P45983-4; Sequence=VSP_004831, VSP_004832; SIMILARITY: Belongs to the Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P45983 Reactome 139918 http://www.reactome.org 12591950 Pubmed 2003 JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis Lei, K Davis, RJ Proc Natl Acad Sci U S A 100:2432-7 Translocation of BIM to mitochondria Translocation of BIM to mitochondria At the beginning of this reaction, 1 molecule of 'BIM' is present. At the end of this reaction, 1 molecule of 'BIM' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 Reactome 139919 http://www.reactome.org Reactome 111446 http://www.reactome.org 14764673 Pubmed 2004 B cell receptor-mediated apoptosis of human lymphocytes is associated with a new regulatory pathway of Bim isoform expression. Mouhamad, S Besnault, L Auffredou, MT Leprince, C Bourgeade, MF Leca, G Vazquez, A J Immunol 172:2084-91 Activation of BMF and translocation to mitochondria Activation of BMF and translocation to mitochondria In healthy cells, BMF is bound to the myosin V motor complex through its interaction with DLC2. UV irradiation or anoikis induces MAPK8 (JNK) to phosphorylate Dynein Light Chain 2 (DLC2) to release BMF. Phosphorylation of DLC2 by MAPK-8 Phosphorylation of DLC2 by MAPK-8 At the beginning of this reaction, 1 molecule of 'BMF sequestered to dynein (DLC2)' is present. At the end of this reaction, 1 molecule of 'phospho-dynein(DLC2) on microtubules', and 1 molecule of 'BMF' are present.<br><br> This reaction takes place on the 'plasma membrane' and is mediated by the 'kinase activity' of 'Mitogen-activated protein kinase 8 '.<br> 1 BMF sequestered to dynein (DLC2) [plasma membrane] BMF sequestered to dynein (DLC2) 1 UniProt:Q96LC9 BMF protein BMF protein UniProt Q96LC9 1 UniProt:Q96FJ2 DLC1 UniProt Q96FJ2 1 1 phospho-dynein(DLC2) on microtubules [plasma membrane] phospho-dynein(DLC2) on microtubules 1 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome 139908 http://www.reactome.org Translocation of BMF to mitochondria Translocation of BMF to mitochondria At the beginning of this reaction, 1 molecule of 'BMF' is present. At the end of this reaction, 1 molecule of 'BMF' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 Reactome 139909 http://www.reactome.org Reactome 139910 http://www.reactome.org Reactome 114452 http://www.reactome.org BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members Interaction of BAD with BCL2 Interaction of BAD with BCL2 At the beginning of this reaction, 1 molecule of 'Bcl-2 protein', and 1 molecule of 'BAD protein' are present. At the end of this reaction, 1 molecule of 'BAD:BCL-2' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 Reactome 114277 http://www.reactome.org Interaction of BAD with BCL-xl Interaction of BAD with BCL-xl At the beginning of this reaction, 1 molecule of 'BAD protein', and 1 molecule of 'Apoptosis regulator Bcl-X' are present. At the end of this reaction, 1 molecule of 'BAD:BCL-xl' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 UniProt:Q07817-1 Apoptosis regulator Bcl-X (Bcl-2-like 1 protein) BCL2L BCLX BCL2L1 FUNCTION: Potent inhibitor of cell death. Isoform Bcl-X(L) anti- apoptotic activity is inhibited by association with SIVA isoform 1. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channnel (VDAC) by binding to it and preventing the release of the caspase activator, cytochrome c, from the mitochondrial membrane. The Bcl-X(S) isoform promotes apoptosis. SUBUNIT: Bcl-X(L) forms heterodimers with BAX, BAK and Bcl-2. Heterodimerization with BAX does not seem to be required for anti- apoptotic activity. Isoform Bcl-X(L) binds to Siva isoform 1. SUBCELLULAR LOCATION: Mitochondrial membranes and perinuclear envelope (By similarity). ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=3; Name=Bcl-X(L); IsoId=Q07817-1; Sequence=Displayed; Name=Bcl-X(S); IsoId=Q07817-2; Sequence=VSP_000515; Name=Bcl-X(beta); IsoId=Q07817-3; Sequence=VSP_000516; TISSUE SPECIFICITY: Bcl-X(S) is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, Bcl-X(L) is found in tissues containing long-lived postmitotic cells, such as adult brain. DOMAIN: The BH4 domain is required for anti-apoptotic activity. The BH1 and BH2 domains are required for both heterodimerization with other Bcl-2 family members and for repression of cell death. PTM: Proteolytically cleaved by caspases during apoptosis. The cleaved protein, lacking the BH4 domain, has pro-apoptotic activity. SIMILARITY: Belongs to the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 1 (BH1) domain. SIMILARITY: Contains 1 Bcl-2 homology 2 (BH2) domain. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. SIMILARITY: Contains 1 Bcl-2 homology 4 (BH4) domain. UniProt Q07817 1 BAD:BCL-xl [mitochondrial outer membrane] BAD:BCL-xl 1 1 Reactome 114276 http://www.reactome.org Sequestration of tBID by BCL-2 Sequestration of tBID by BCL-2 At the beginning of this reaction, 1 molecule of 'Bcl-2 protein', and 1 molecule of 'tBID' are present. At the end of this reaction, 1 molecule of 'tBID:BCL-2' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 Reactome 114352 http://www.reactome.org 12624108 Pubmed 2003 Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed. Yi, X Yin, XM Dong, Z J Biol Chem 278:16992-9 Interaction of tBID with BCL-xl Interaction of tBID with BCL-xl At the beginning of this reaction, 1 molecule of 'tBID', and 1 molecule of 'Apoptosis regulator Bcl-X' are present. At the end of this reaction, 1 molecule of 'tBID:BCL-xl' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 tBID:BCL-xl [mitochondrial outer membrane] tBID:BCL-xl 1 1 Reactome 114365 http://www.reactome.org Interaction of BIM with BCL2 Interaction of BIM with BCL2 At the beginning of this reaction, 1 molecule of 'BIM', and 1 molecule of 'Bcl-2 protein' are present. At the end of this reaction, 1 molecule of 'BIM:BCL2' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 BIM:BCL2 [mitochondrial outer membrane] BIM:BCL2 1 1 Reactome 114279 http://www.reactome.org 10198631 Pubmed 1999 The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex Puthalakath, H Huang, DC O'Reilly, LA King, SM Strasser, A Mol Cell 3:287-96 Interaction of BIM with BCL-xl Interaction of BIM with BCL-xl At the beginning of this reaction, 1 molecule of 'BIM', and 1 molecule of 'Apoptosis regulator Bcl-X' are present. At the end of this reaction, 1 molecule of 'BIM:BCL-xl' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 BIM:BCL-xl [mitochondrial outer membrane] BIM:BCL-xl 1 1 Reactome 114278 http://www.reactome.org Interaction of NOXA with BCL2 Interaction of NOXA with BCL2 At the beginning of this reaction, 1 molecule of 'Bcl-2 protein', and 1 molecule of 'NOXA protein' are present. At the end of this reaction, 1 molecule of 'NOXA:BCL2' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 NOXA:BCL2 [mitochondrial outer membrane] NOXA:BCL2 1 1 Reactome 114241 http://www.reactome.org Interaction of PUMA and Bcl-2 Interaction of PUMA and Bcl-2 At the beginning of this reaction, 1 molecule of 'Bcl-2 protein', and 1 molecule of 'PUMA protein' are present. At the end of this reaction, 1 molecule of 'PUMA:Bcl-2 complex' is present.<br><br> This reaction takes place in the 'mitochondrial envelope'.<br> 1 1 1 PUMA:Bcl-2 complex [mitochondrial outer membrane] PUMA:Bcl-2 complex 1 1 Reactome 140230 http://www.reactome.org Interaction of PUMA and Bcl-XL Interaction of PUMA and Bcl-XL At the beginning of this reaction, 1 molecule of 'PUMA protein', and 1 molecule of 'Apoptosis regulator Bcl-X' are present. At the end of this reaction, 1 molecule of 'PUMA:Bcl-XL complex' is present.<br><br> This reaction takes place in the 'mitochondrial envelope'.<br> 1 1 1 PUMA:Bcl-XL complex [mitochondrial outer membrane] PUMA:Bcl-XL complex 1 1 Reactome 140232 http://www.reactome.org Interaction of NOXA with BCL-xl Interaction of NOXA with BCL-xl At the beginning of this reaction, 1 molecule of 'NOXA protein', and 1 molecule of 'Apoptosis regulator Bcl-X' are present. At the end of this reaction, 1 molecule of 'NOXA:BCL-xl' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 1 1 NOXA:BCL-xl [mitochondrial outer membrane] NOXA:BCL-xl 1 1 Reactome 114281 http://www.reactome.org Reactome 111453 http://www.reactome.org Activation, translocation and oligomerization of BAX Activation, translocation and oligomerization of BAX tBID activates BAX protein tBID activates BAX protein 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. 1 tBID bound to inactive BAX [cytosol] tBID bound to inactive BAX 1 1 UniProt:Q07812-1 Apoptosis regulator BAX, membrane isoform alpha BAX FUNCTION: Accelerates programmed cell death by binding to, and antagonizing the apoptosis repressor BCL2 or its adenovirus homolog E1B 19k protein. Induces the release of cytochrome c, activation of CASP3, and thereby apoptosis. SUBUNIT: Homodimers and heterodimers with BCL2, E1B 19K protein, BCL2L1 isoform Bcl-X(L), MCL1 and A1. Interacts with SH3GLB1 and HN. SUBCELLULAR LOCATION: Membrane-bound. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=4; Name=Alpha; IsoId=Q07812-1; Sequence=Displayed; Name=Beta; IsoId=Q07812-2; Sequence=Not described; Name=Gamma; IsoId=Q07812-4; Sequence=Not described; Name=Delta; IsoId=Q07812-3; Sequence=Not described; TISSUE SPECIFICITY: Expressed in a wide variety of tissues. DOMAIN: Intact BH3 domain is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family (By similarity). DISEASE: Defects in BAX are found in some cell lines from hematopoietic malignancies as T-cell acute lymphoblastic leukemia, Burkitt lymphoma, and plasmacytoma. SIMILARITY: Belongs to the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 1 (BH1) domain. SIMILARITY: Contains 1 Bcl-2 homology 2 (BH2) domain. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. UniProt Q07812 1 1 Reactome 139917 http://www.reactome.org 10629050 Pubmed 2000 Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane Eskes, R Desagher, S Antonsson, B Martinou, JC Mol Cell Biol 20:929-35 10085289 Pubmed 1999 Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis Desagher, S Osen-Sand, A Nichols, A Eskes, R Montessuit, S Lauper, S Maundrell, K Antonsson, B Martinou, JC J Cell Biol 144:891-901 Translocation of activated BAX to the mitochondria Translocation of activated BAX to the mitochondria At the beginning of this reaction, 1 molecule of 'Activated BAX' is present. At the end of this reaction, 1 molecule of 'Activated BAX inserted into mitochondrial membrane' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 Reactome 114264 http://www.reactome.org 12176904 Pubmed 2002 Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. Bellosillo, B Villamor, N López-Guillermo, A Marcé, S Bosch, F Campo, E Montserrat, E Colomer, D Blood 100:1810-6 11136736 Pubmed 2001 Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. Antonsson, B Montessuit, S Sanchez, B Martinou, JC J Biol Chem 276:11615-23 Oligomerization of BAX at the mitochondrial membrane Oligomerization of BAX at the mitochondrial membrane At the beginning of this reaction, 2 molecules of 'Activated BAX inserted into mitochondrial membrane' is present. At the end of this reaction, 1 molecule of 'Activated BAX' is present.<br><br> This reaction takes place in the 'mitochondrial envelope'.<br> 2 1 Activated BAX [mitochondrial outer membrane] Activated BAX 2 Reactome 114275 http://www.reactome.org tBID binds to inactive BAX protein tBID binds to inactive BAX protein At the beginning of this reaction, 1 molecule of 'tBID-p15', and 1 molecule of 'Inactive Bax alpha protein' are present. At the end of this reaction, 1 molecule of 'tBID bound to inactive BAX' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 1 Reactome 168849 http://www.reactome.org Reactome 114294 http://www.reactome.org Activation and oligomerization of BAK protein Activation and oligomerization of BAK protein tBID activates BAK protein tBID activates BAK 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 BAX induces intramembranous oligomerization leading to a pore for cytochrome c efflux. 1 tBID bound to inactive BAK [mitochondrial outer membrane] tBID bound to inactive BAK 1 1 UniProt:Q16611 Bcl-2 homologous antagonist/killer (Apoptosis regulator BAK) (BCL2- like 7 protein) BCL2L7 BAK BAK1 FUNCTION: In the presence of an appropriate stimulus, accelerates programmed cell death by binding to, and antagonizing the a repressor Bcl-2 or its adenovirus homolog E1B 19k protein. SUBUNIT: Forms heterodimers with Bcl-2, E1B 19k protein, and Bcl- X(L). SUBCELLULAR LOCATION: Membrane-bound (Potential). TISSUE SPECIFICITY: Expressed in a wide variety of tissues, with highest levels in the heart and skeletal muscle. DOMAIN: Intact BH3 domain is required by BIK, BID, BAK, BAD and BAX for their pro-apoptotic activity and for their interaction with anti-apoptotic members of the Bcl-2 family. SIMILARITY: Belongs to the Bcl-2 family. SIMILARITY: Contains 1 Bcl-2 homology 1 (BH1) domain. SIMILARITY: Contains 1 Bcl-2 homology 2 (BH2) domain. SIMILARITY: Contains 1 Bcl-2 homology 3 (BH3) domain. UniProt Q16611 1 1 Reactome 139895 http://www.reactome.org 10950869 Pubmed 2000 tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c Wei, MC Lindsten, T Mootha, VK Weiler, S Gross, A Ashiya, M Thompson, CB Korsmeyer, SJ Genes Dev 14:2060-71 Oligomerization of BAK at the mitochondrial membrane Oligomerization of BAK at the mitochondrial membrane At the beginning of this reaction, 2 molecules of 'Activated BAK protein' is present. At the end of this reaction, 1 molecule of 'Active oligomeric BAK' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 2 1 Active oligomeric BAK [mitochondrial outer membrane] Active oligomeric BAK 2 Reactome 114263 http://www.reactome.org 12721291 Pubmed 2003 BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. Ruffolo, SC Shore, GC J Biol Chem 278:25039-45 tBID binds to inactive BAK protein tBID binds to inactive BAK 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 BAX induces intramembranous oligomerization leading to a pore for cytochrome c efflux. 1 1 1 Reactome 168848 http://www.reactome.org Reactome 111452 http://www.reactome.org Permeabilization of mitochondria Permeabilization of mitochondria Activation and oligomerization of Bax and Bak result in the destabilization of the outer mitochondrial membrane. This results in the release of the apoptotic factors Cytochrome c and SMAC from the intermembrane space. Reactome 111455 http://www.reactome.org 11711427 Pubmed 2001 The expanding role of mitochondria in apoptosis. Wang, X Genes Dev 15:2922-33 12941691 Pubmed 2003 Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization. Arnoult, D Gaume, B Karbowski, M Sharpe, JC Cecconi, F Youle, RJ EMBO J 22:4385-99 Release of apoptotic factors from the mitochondria Release of apoptotic factors from the mitochondria Apoptotic factors released from the mitochondria promote apoptosis through several different mechanisms. Cytochrome C participates in Apoptosome driven effector caspase activation while SMAC relieves IAP mediated caspase inhibition. Release of Cytochrome c from mitochondria Release of Cytochrome c from mitochondria At the beginning of this reaction, 1 molecule of 'Cytochrome c' is present. At the end of this reaction, 1 molecule of 'Cytochrome c' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 mitochondrial intermembrane space GO 0005758 UniProt:P99999 Cytochrome c CYCS CYC FUNCTION: Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. FUNCTION: Plays a role in apoptosis. Suppression of the anti- apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases. SUBCELLULAR LOCATION: Mitochondrial matrix. PTM: Binds 1 heme group per subunit. SIMILARITY: Belongs to the cytochrome c family. UniProt P99999 1 Reactome 114284 http://www.reactome.org 12660240 Pubmed 2003 Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. Song, Z Yao, X Wu, M J Biol Chem 278:23130-40 Release of SMAC from mitochondria Release of SMAC from mitochondria At the beginning of this reaction, 1 molecule of 'Smac protein, mitochondrial precursor' is present. At the end of this reaction, 1 molecule of 'SMAC' is present.<br><br> This reaction takes place in the 'mitochondrial outer membrane'.<br> 1 UniProt:Q9NR28-1 Diablo homolog, mitochondrial precursor (Second mitochondria-derived activator of caspase) (Smac protein) (Direct IAP binding protein with low pI) SMAC DIABLO FUNCTION: Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway. Acts by opposing the inhibitory activity of inhibitor of apoptosis proteins (IAP). SUBUNIT: Homodimer. Interacts with BIRC2, BIRC3, BIRC4/XIAP and BIRC7. SUBCELLULAR LOCATION: Mitochondrial but released into the cytosol when cells undergo apoptosis. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q9NR28-1; Sequence=Displayed; Name=2; Synonyms=Diablo-S; IsoId=Q9NR28-2; Sequence=VSP_004397; TISSUE SPECIFICITY: Ubiquitously expressed with highest expression in testis. Expression is also high in heart, liver, kidney, spleen, prostate and ovary. Low in brain, lung, thymus and peripheral blood leukocytes. DOMAIN: The mature N-terminus mediates interaction with BIRC4/XIAP. UniProt Q9NR28 1 Reactome 114307 http://www.reactome.org Reactome 111457 http://www.reactome.org 10913597 Pubmed 2000 Apoptosis-inducing factor (AIF): a ubiquitous mitochondrial oxidoreductase involved in apoptosis. Daugas, E Nochy, D Ravagnan, L Loeffler, M Susin, SA Zamzami, N Kroemer, G FEBS Lett 476:118-23 15077149 Pubmed 2004 Toxic proteins released from mitochondria in cell death. Saelens, X Festjens, N Vande Walle, L van Gurp, M van Loo, G Vandenabeele, P Oncogene 23:2861-74 Apoptotic factor-mediated response Apoptotic factor-mediated response Cytochrome c-mediated apoptotic response Cytochrome c-mediated apoptotic response Upon its release from the mitochondrial intermembrane space, Cytochrome c binds to and causes a conformational change in the cytoplasmic protein Apaf1. This conformational change allows the Cytochrome c:Apaf1 complex to associate with ATP triggering oligomerization of the Apaf1:Cytochrome c:ATP complex. The apoptosome then associates with Procaspase-9 resulting in the formation of the active caspase-9 holoenzyme which functions in cleaving effector caspases. Formation of apoptosome Formation of apoptosome Cytochrome C Binds to Apaf-1 Cytochrome C Binds to Apaf-1 At the beginning of this reaction, 1 molecule of 'Cytochrome c', and 1 molecule of 'Apaf-1' are present. At the end of this reaction, 1 molecule of 'Apaf-1:Cytochrome C' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 UniProt:O14727-1 Apoptotic protease activating factor 1 (Apaf-1) KIAA0413 APAF1 FUNCTION: Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis. This activation requires ATP. Isoform 6 is less effective in inducing apoptosis. SUBUNIT: Monomer. Oligomerizes upon binding of cytochrome c and dATP. Oligomeric Apaf-1 and pro-caspase-9 bind to each other via their respective NH2-terminal CARD domains and consecutively mature caspase-9 is released from the complex. Pro-caspase-3 is recruited into the Apaf-1-pro-caspase-9 complex via interaction with pro-caspase-9. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=6; Name=1; Synonyms=Apaf-1XL; IsoId=O14727-1; Sequence=Displayed; Name=2; Synonyms=Apaf-1L; IsoId=O14727-2; Sequence=VSP_006759; Name=3; Synonyms=Apaf-1S; IsoId=O14727-3; Sequence=VSP_006759, VSP_006761; Name=4; Synonyms=Apaf-1M; IsoId=O14727-4; Sequence=VSP_006761; Name=5; Synonyms=Apaf-1XS; IsoId=O14727-5; Sequence=VSP_006760, VSP_006761, VSP_006762; Name=6; Synonyms=Apaf-1-ALT; IsoId=O14727-6; Sequence=VSP_008965, VSP_008966; TISSUE SPECIFICITY: Ubiquitous. Highest levels of expression in adult spleen and peripheral blood leukocytes, and in fetal brain, kidney and lung. Isoform 1 is expressed in heart, kidney and liver. INDUCTION: By E2F and p53 in apoptotic neurons. SIMILARITY: Contains 1 CARD domain. SIMILARITY: Contains 1 NB-ARC domain. SIMILARITY: Contains 13 WD repeats. CAUTION: Ref.7 sequence differs from that shown due to a frameshift in position 109. UniProt O14727 1 Apaf-1:Cytochrome C [cytosol] Apaf-1:Cytochrome C 1 1 Reactome 114254 http://www.reactome.org 9267021 Pubmed 1997 Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Zou, H Henzel, WJ Liu, X Lutschg, A Wang, X Cell 90:405-13 Cytochrome C:Apaf-1 binds Procaspase-9 Cytochrome C:Apaf-1 binds Procaspase-9 At the beginning of this reaction, 1 molecule of 'Caspase-9 precursor ', and 1 molecule of 'Apaf-1:Cytochrome C' are present. At the end of this reaction, 1 molecule of 'Cytochrome C:Apaf-1:Procaspase-9' is present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 UniProt:P55211-1 Caspase-9 precursor (EC 3.4.22.-) (CASP-9) (ICE-like apoptotic protease 6) (ICE-LAP6) (Apoptotic protease Mch-6) (Apoptotic protease activating factor 3) (APAF-3) CASP9 MCH6 FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf- 1 leads to activation of the protease which then cleaves and activates caspase-3. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). FUNCTION: Isoform 2 lacks activity is an dominant-negative inhibitor of caspase-9. SUBUNIT: Heterodimer of a 35 kDa (P35) and a 10 kDa (P10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2- terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts with BIRC7. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=2; Name=1; Synonyms=9L, Alpha; IsoId=P55211-1; Sequence=Displayed; Name=2; Synonyms=9S, Beta; IsoId=P55211-2; Sequence=VSP_000818; TISSUE SPECIFICITY: Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. PTM: Cleavages at Asp-315 by granzyme B and at Asp-330 by CPP32 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events. SIMILARITY: Belongs to the peptidase C14 family. SIMILARITY: Contains 1 CARD domain. UniProt P55211 1 1 Cytochrome C:Apaf-1:Procaspase-9 [cytosol] Cytochrome C:Apaf-1:Procaspase-9 1 1 Reactome 114256 http://www.reactome.org 9390557 Pubmed 1997 Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Li, P Nijhawan, D Budihardjo, I Srinivasula, SM Ahmad, M Alnemri, ES Wang, X Cell 91:479-89 Cleavage of Procaspase-9 to Caspase-9 Cleavage of Procaspase-9 to Caspase-9 At the beginning of this reaction, 1 molecule of 'Cytochrome C:Apaf-1:Procaspase-9' is present. At the end of this reaction, 1 molecule of 'Apoptosome' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'caspase activity' of 'Apoptosome'.<br> 1 1 Apoptosome [cytosol] Apoptosome Cytochrome C:Apaf-1:Caspase-9 1 1 Cleaved Caspase-9 [cytosol] Cleaved Caspase-9 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome 114259 http://www.reactome.org Reactome 111458 http://www.reactome.org 15184073 Pubmed 2004 Apo cytochrome c inhibits caspases by preventing apoptosome formation. Martin, AG Nguyen, J Wells, JA Fearnhead, HO Biochem Biophys Res Commun 319:944-50 Activation of caspases through apoptosome-mediated cleavage Activation of caspases through apoptosome-mediated cleavage Cleavage of Procaspase-3 by the apoptosome Cleavage of Procaspase-3 by the apoptosome At the beginning of this reaction, 1 molecule of 'Apopain precursor ' is present. At the end of this reaction, 1 molecule of 'Active caspase-3' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'caspase activity' of 'Apoptosome'.<br> 1 UniProt:P42574 Caspase-3 precursor (EC 3.4.22.-) (CASP-3) (Apopain) (Cysteine protease CPP32) (Yama protein) (CPP-32) (SREBP cleavage activity 1) (SCA-1) CASP3 CPP32 FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a 216-Asp-|-Gly-217 bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop- helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. ENZYME REGULATION: Inhibited by isatin sulfonamides. SUBUNIT: Heterodimer of a 17 kDa (p17) and a 12 kDa (p12) subunit. SUBCELLULAR LOCATION: Cytoplasmic. TISSUE SPECIFICITY: Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system. PTM: Cleavage by granzyme b, APAF-1, caspase-6, -8 and -10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of CPP32 also occur and vice versa. SIMILARITY: Belongs to the peptidase C14 family. UniProt P42574 1 Active caspase-3 [cytosol] Active caspase-3 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome 114252 http://www.reactome.org 10206961 Pubmed 1999 An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. Zou, H Li, Y Liu, X Wang, X J Biol Chem 274:11549-56 Cleavage of Procaspase-7 by the apoptosome Cleavage of Procaspase-7 by the apoptosome At the beginning of this reaction, 1 molecule of 'Caspase-7 precursor ' is present. At the end of this reaction, 1 molecule of 'Active Caspase-7' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'caspase activity' of 'Apoptosome'.<br> 1 UniProt:P55210-1 Caspase-7 precursor (EC 3.4.22.-) (CASP-7) (ICE-like apoptotic protease 3) (ICE-LAP3) (Apoptotic protease Mch-3) (CMH-1) MCH3 CASP7 FUNCTION: Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a 216-Asp-|-Gly-217 bond. Overexpression promotes programmed cell death. ENZYME REGULATION: Inhibited by isatin sulfonamides. SUBUNIT: Heterodimer of a 20 kDa (p20) and a 11 kDa (p11) subunit. SUBCELLULAR LOCATION: Cytoplasmic. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=3; Name=Alpha; IsoId=P55210-1; Sequence=Displayed; Name=Beta; IsoId=P55210-2; Sequence=VSP_000807; Note=Not proteolytically active; Name=Alpha'; Synonyms=Beta; IsoId=P55210-3; Sequence=VSP_000806; Note=What we call isoform Alpha' is known in Ref.4 as Beta; TISSUE SPECIFICITY: Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain. PTM: Cleavages by granzyme B or caspase-10 generate the two active subunits. Propeptide domains can also be cleaved efficiently by CPP32 protease. Active heterodimers between the small subunit of caspase-7 and the large subunit of CPP32 protease, and vice versa, also occur. SIMILARITY: Belongs to the peptidase C14 family. UniProt P55210 1 Active Caspase-7 [cytosol] Active Caspase-7 1 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome 114261 http://www.reactome.org 9922454 Pubmed 1999 Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. Slee, EA Harte, MT Kluck, RM Wolf, BB Casiano, CA Newmeyer, DD Wang, HG Reed, JC Nicholson, DW Alnemri, ES Green, DR Martin, SJ J Cell Biol 144:281-92 Reactome 111459 http://www.reactome.org GO 0008635 GO biological process Reactome 111461 http://www.reactome.org SMAC-mediated apoptotic response SMAC-mediated apoptotic response Once released from the mitochondria, SMAC binds to IAP family proteins displacing them from Caspase:IAP complexes liberating the active caspases. SMAC binds to IAPs SMAC binds to IAPs SMAC binds XIAP:Caspase-3 SMAC binds XIAP:Caspase-3 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.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 XIAP:Caspase-3 [cytosol] XIAP:Caspase-3 1 1 UniProt:P98170 Baculoviral IAP repeat-containing protein 4 (Inhibitor of apoptosis protein 3) (X-linked inhibitor of apoptosis protein) (X-linked IAP) (IAP-like protein) (HILP) XIAP BIRC4 IAP3 API3 FUNCTION: Apoptotic suppressor. Inhibitor of caspase-3, -7 and -9. SUBUNIT: Interacts with SMAC and with PRSS25; these interactions inhibit apoptotic suppressor activity. SUBCELLULAR LOCATION: Cytoplasmic. TISSUE SPECIFICITY: Ubiquitous, except peripheral blood leukocytes. DOMAIN: The second BIR domain is sufficient to inhibit caspase-3 and -7, while the third BIR is involved in caspase-9 inhibition. The interactions with SMAC and PRSS25 are mediated by the second and third BIR domains. SIMILARITY: Belongs to the IAP family. SIMILARITY: Contains 3 BIR repeats. SIMILARITY: Contains 1 RING-type zinc finger. UniProt P98170 1 SMAC:XIAP:Caspase-3 [cytosol] SMAC:XIAP:Caspase-3 1 1 Reactome 114306 http://www.reactome.org 14960576 Pubmed 2004 Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells. Yang, QH Du, C J Biol Chem 279:16963-70 9230442 Pubmed 1997 X-linked IAP is a direct inhibitor of cell-death proteases. Deveraux, QL Takahashi, R Salvesen, GS Reed, JC Nature 388:300-4 11257231 Pubmed 2001 Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain. Huang, Y Park, YC Rich, RL Segal, D Myszka, DG Wu, H Cell 104:781-90 SMAC binds XIAP:Caspase-7 SMAC binds XIAP:Caspase-7 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.<br><br> This reaction takes place in the 'cytosol'.<br> 1 XIAP:Caspase-7 [cytosol] XIAP:Caspase-7 1 1 1 1 SMAC:XIAP:Caspase-7 [cytosol] SMAC:XIAP:Caspase-7 1 1 Reactome 114354 http://www.reactome.org SMAC binds XIAP:Caspase-9 SMAC binds XIAP:Caspase-9 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.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 XIAP:Caspase-9 [cytosol] XIAP:Caspase-9 1 1 1 SMAC:XIAP:Caspase-9 [cytosol] SMAC:XIAP:Caspase-9 1 1 Reactome 114361 http://www.reactome.org 11084335 Pubmed 2000 ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Vucic, D Stennicke, HR Pisabarro, MT Salvesen, GS Dixit, VM Curr Biol 10:1359-66 Reactome 111463 http://www.reactome.org SMAC-mediated dissociation of IAP:caspase complexes SMAC-mediated dissociation of IAP:caspase complexes Dissociation of Caspase-3 from SMAC:XIAP:Caspase-3 Dissociation of Caspase-3 from SMAC:XIAP:Caspase-3 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-3' is present. At the end of this reaction, 1 molecule of 'Active caspase-3', and 1 molecule of 'SMAC:XIAP' are present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 1 SMAC:XIAP [cytosol] SMAC:XIAP 1 1 Reactome 114419 http://www.reactome.org Dissociation of Caspase-7 from SMAC:XIAP:Caspase-7 Dissociation of Caspase-7 from SMAC:XIAP:Caspase-7 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-7' is present. At the end of this reaction, 1 molecule of 'SMAC:XIAP', and 1 molecule of 'Active Caspase-7' are present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 1 Reactome 114392 http://www.reactome.org Dissociation of Caspase-9 from SMAC:XIAP:Caspase-9 Dissociation of Caspase-9 from SMAC:XIAP:Caspase-9 At the beginning of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-9' is present. At the end of this reaction, 1 molecule of 'Cleaved Caspase-9', and 1 molecule of 'SMAC:XIAP' are present.<br><br> This reaction takes place in the 'cytosol'.<br> 1 1 1 Reactome 114440 http://www.reactome.org Reactome 111464 http://www.reactome.org Reactome 111469 http://www.reactome.org 12042762 Pubmed 2002 IAP proteins: blocking the road to death's door. Salvesen, GS Duckett, CS Nat Rev Mol Cell Biol 3:401-10 Reactome 111471 http://www.reactome.org Reactome 109606 http://www.reactome.org 14561771 Pubmed 2003 Ways of dying: multiple pathways to apoptosis. Adams, JM Genes Dev 17:2481-95 GO 0008629 GO biological process Activation of Effector Caspases Activation of Effector Caspases Reactome 75142 http://www.reactome.org Apoptotic execution phase Apoptotic execution phase Cleavage of cellular proteins by active caspases Cleavage of cellular proteins by active caspases Reactome 111465 http://www.reactome.org Apoptosis induced DNA fragmentation Apoptosis induced DNA fragmentation Reactome 140342 http://www.reactome.org GO 0006309 GO biological process Reactome 75153 http://www.reactome.org Reactome 109581 http://www.reactome.org 12505355 Pubmed 2002 History of the events leading to the formulation of the apoptosis concept Kerr, JF Toxicology 181:471-4 12189384 Pubmed 2002 Targeting death and decoy receptors of the tumour-necrosis factor superfamily Ashkenazi, A Nat Rev Cancer 2:420-30 4561027 Pubmed 1972 Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics Kerr, JF Wyllie, AH Currie, AR Br J Cancer 26:239-57 15218528 Pubmed 2004 Apoptosis and disease: a life or death decision MacFarlane, M Williams, AC EMBO Rep 5:674-8 GO 0006915 GO biological process