Caspase-9

Caspase 9, apoptosis-related cysteine peptidase
PDB rendering based on 1jxq.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1JXQ​, 1NW9​, 2AR9​, 3D9T​, 3V3K​, 3YGS​, 4RHW​
Identifiers
Symbols	CASP9 ; APAF-3; APAF3; ICE-LAP6; MCH6; PPP1R56
External IDs	OMIM: 602234 MGI: 1277950 HomoloGene: 31024 ChEMBL: 2273 GeneCards: CASP9 Gene
EC number	3.4.22.62
Gene ontology Molecular function • cysteine-type endopeptidase activity • protein binding • enzyme activator activity • peptidase activity • SH3 domain binding • protein kinase binding • cysteine-type endopeptidase activity involved in apoptotic signaling pathway Cellular component • nucleus • cytoplasm • mitochondrion • cytosol • apoptosome Biological process • apoptotic process • cellular response to DNA damage stimulus • epidermal growth factor receptor signaling pathway • aging • fibroblast growth factor receptor signaling pathway • intrinsic apoptotic signaling pathway in response to DNA damage • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • programmed cell death • platelet formation • response to cobalt ion • response to estradiol • response to lipopolysaccharide • glial cell apoptotic process • cellular response to UV • Fc-epsilon receptor signaling pathway • signal transduction in response to DNA damage • positive regulation of neuron apoptotic process • innate immune response • response to antibiotic • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • cellular response to dexamethasone stimulus • extrinsic apoptotic signaling pathway • extrinsic apoptotic signaling pathway in absence of ligand • intrinsic apoptotic signaling pathway • regulation of response to DNA damage stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	842	12371
Ensembl	ENSG00000132906	ENSMUSG00000028914
UniProt	P55211	Q8C3Q9
RefSeq (mRNA)	NM_001229	NM_001277932
RefSeq (protein)	NP_001220	NP_001264861
Location (UCSC)	Chr 1: 15.49 – 15.53 Mb	Chr 4: 141.79 – 141.82 Mb
PubMed search

Caspase-9 is an initiator caspase,^[1] encoded by the CASP9 gene. CASP9 orthologs ^[2] have been identified in all mammals for which complete genome data are available. Unique orthologs are also present in lizards, lissamphibians, and teleosts.

The aspartic acid specific protease caspase-9 has been linked to the mitochondrial death pathway. It is activated during programmed cell death (apoptosis). Induction of stress signaling pathways JNK/SAPK causes release of cytochrome c from mitochondria and activation of apaf-1 (apoptosome), which in turn cleaves the pro-enzyme of caspase-9 into the active form.

Once initiated caspase-9 goes on to cleave procaspase-3 & procaspase-7, which cleave several cellular targets, including poly ADP ribose polymerase.

Structure

Caspase-9 precursor procaspase-9 is present as an inactive monomer before it undergoes a conformational change to a dimer and associates with the apf-1 and cytochrome c complex to form an apoptosome.^[3]

Interactions

Caspase-9 has been shown to interact with:

• APAF1^{[4][5][6][7][8]}
• BIRC2,^[9]
• Baculoviral IAP repeat-containing protein 3,^[9]
• Caspase 8,^[10][11]
• NLRP1,^[4][12] and
• XIAP.^{[9][13][14][15]}

Overview of signal transduction pathways involved in apoptosis.

See also

• The Proteolysis Map
• Caspase

References

1. Caspase 9
2. "OrthoMaM phylogenetic marker: CASP9 coding sequence".
3. Bratton, Shawn; Salvesen, Guy (2010). "Regulation of the Apaf-1-caspase-9 apoptosome". Journal of Cell Science 123: 3209–3214. doi:10.1242/jcs.073643. Retrieved 27 September 2015.
4. Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC (March 2001). "A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis". J. Biol. Chem. 276 (12): 9239–45. doi:10.1074/jbc.M006309200. PMID 11113115.
5. Cho DH, Hong YM, Lee HJ, Woo HN, Pyo JO, Mak TW, Jung YK (September 2004). "Induced inhibition of ischemic/hypoxic injury by APIP, a novel Apaf-1-interacting protein". J. Biol. Chem. 279 (38): 39942–50. doi:10.1074/jbc.M405747200. PMID 15262985.
6. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (November 1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell 91 (4): 479–89. doi:10.1016/s0092-8674(00)80434-1. PMID 9390557.
7. Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (April 1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proc. Natl. Acad. Sci. U.S.A. 95 (8): 4386–91. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
8. Pan G, O'Rourke K, Dixit VM (March 1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". J. Biol. Chem. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.
9. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (April 1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. 17 (8): 2215–23. doi:10.1093/emboj/17.8.2215. PMC 1170566. PMID 9545235.
10. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (April 2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". J. Biol. Chem. 277 (16): 13430–7. doi:10.1074/jbc.M108029200. PMID 11832478.
11. Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (December 1996). "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases". Proc. Natl. Acad. Sci. U.S.A. 93 (25): 14486–91. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
12. Hlaing T, Guo RF, Dilley KA, Loussia JM, Morrish TA, Shi MM, Vincenz C, Ward PA (March 2001). "Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins". J. Biol. Chem. 276 (12): 9230–8. doi:10.1074/jbc.M009853200. PMID 11076957.
13. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
14. Davoodi J, Lin L, Kelly J, Liston P, MacKenzie AE (September 2004). "Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9". J. Biol. Chem. 279 (39): 40622–8. doi:10.1074/jbc.M405963200. PMID 15280366.
15. Richter BW, Mir SS, Eiben LJ, Lewis J, Reffey SB, Frattini A, Tian L, Frank S, Youle RJ, Nelson DL, Notarangelo LD, Vezzoni P, Fearnhead HO, Duckett CS (July 2001). "Molecular cloning of ILP-2, a novel member of the inhibitor of apoptosis protein family". Mol. Cell. Biol. 21 (13): 4292–301. doi:10.1128/MCB.21.13.4292-4301.2001. PMC 87089. PMID 11390657.

Further reading

• Cohen GM (1997). "Caspases: the executioners of apoptosis". Biochem. J. 326 (Pt 1): 1–16. PMC 1218630. PMID 9337844.
• Deveraux QL, Reed JC (1999). "IAP family proteins--suppressors of apoptosis". Genes Dev. 13 (3): 239–52. doi:10.1101/gad.13.3.239. PMID 9990849.
• Zhao LJ, Zhu H (2005). "Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design". Curr. Drug Targets Immune Endocr. Metabol. Disord. 4 (4): 265–75. doi:10.2174/1568008043339668. PMID 15578977.
• Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle". Retrovirology 2: 11. doi:10.1186/1742-4690-2-11. PMC 554975. PMID 15725353.
• Moon HS, Yang JS (2006). "Role of HIV Vpr as a regulator of apoptosis and an effector on bystander cells". Mol. Cells 21 (1): 7–20. PMID 16511342.
• Kopp S (1976). "Reproducibility of response to a questionnaire on symptoms of masticatory dysfunction". Community dentistry and oral epidemiology 4 (5): 205–9. doi:10.1111/j.1600-0528.1976.tb00985.x. PMID 1067155.
• Fernandes-Alnemri T, Litwack G, Alnemri ES (1995). "CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta-converting enzyme". J. Biol. Chem. 269 (49): 30761–4. PMID 7983002.
• Duan H, Orth K, Chinnaiyan AM, Poirier GG, Froelich CJ, He WW, Dixit VM (1996). "ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B". J. Biol. Chem. 271 (28): 16720–4. doi:10.1074/jbc.271.28.16720. PMID 8663294.
• Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996). "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32". J. Biol. Chem. 271 (43): 27099–106. doi:10.1074/jbc.271.43.27099. PMID 8900201.
• Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Litwack G, Alnemri ES (1997). "Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases". Proc. Natl. Acad. Sci. U.S.A. 93 (25): 14486–91. doi:10.1073/pnas.93.25.14486. PMC 26159. PMID 8962078.
• Kothakota S, Azuma T, Reinhard C, Klippel A, Tang J, Chu K, McGarry TJ, Kirschner MW, Koths K, Kwiatkowski DJ, Williams LT (1997). "Caspase-3-generated fragment of gelsolin: effector of morphological change in apoptosis". Science 278 (5336): 294–8. doi:10.1126/science.278.5336.294. PMID 9323209.
• Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997). "Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade". Cell 91 (4): 479–89. doi:10.1016/S0092-8674(00)80434-1. PMID 9390557.
• Pan G, O'Rourke K, Dixit VM (1998). "Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex". J. Biol. Chem. 273 (10): 5841–5. doi:10.1074/jbc.273.10.5841. PMID 9488720.
• Hu Y, Benedict MA, Wu D, Inohara N, Núñez G (1998). "Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation". Proc. Natl. Acad. Sci. U.S.A. 95 (8): 4386–91. doi:10.1073/pnas.95.8.4386. PMC 22498. PMID 9539746.
• Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS, Reed JC (1998). "IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases". EMBO J. 17 (8): 2215–23. doi:10.1093/emboj/17.8.2215. PMC 1170566. PMID 9545235.
• Srinivasula SM, Ahmad M, Fernandes-Alnemri T, Alnemri ES (1998). "Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization". Mol. Cell 1 (7): 949–57. doi:10.1016/S1097-2765(00)80095-7. PMID 9651578.
• Kamada S, Kusano H, Fujita H, Ohtsu M, Koya RC, Kuzumaki N, Tsujimoto Y (1998). "A cloning method for caspase substrates that uses the yeast two-hybrid system: Cloning of the antiapoptotic gene gelsolin". Proc. Natl. Acad. Sci. U.S.A. 95 (15): 8532–7. doi:10.1073/pnas.95.15.8532. PMC 21110. PMID 9671712.
• Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998). "Regulation of cell death protease caspase-9 by phosphorylation". Science 282 (5392): 1318–21. doi:10.1126/science.282.5392.1318. PMID 9812896.
• Hu Y, Ding L, Spencer DM, Núñez G (1999). "WD-40 repeat region regulates Apaf-1 self-association and procaspase-9 activation". J. Biol. Chem. 273 (50): 33489–94. doi:10.1074/jbc.273.50.33489. PMID 9837928.
• Lei K, Nimnual A, Zong WX, Kennedy NJ, Flavell RA, Thompson CB, Bar-Sagi D, Davis RJ (2002). "The Bax Subfamily of Bcl2-Related Proteins Is Essential for Apoptotic Signal Transduction by c-Jun NH2-Terminal Kinase". Mol Cell Biol 22 (13): 4929–42. doi:10.1128/MCB.22.13.4929-4942.2002. PMC 133923. PMID 12052897.
• Earnshaw WC, Martins LM, Kaufmann SH (1999). "Mammalian caspases: structure, activation, substrates, and functions during apoptosis". Annu Rev Biochem 68: 383–424. doi:10.1146/annurev.biochem.68.1.383. PMID 10872455.

External links

• The MEROPS online database for peptidases and their inhibitors: C14.010