CASP9 (Homo sapiens)
Description [+]
- Synonyms: CASP9, CASPASE-9, CASPASE 9, CASP9, MCH6, ICE-LAP6, APAF-3
- Species: Metazoa;Bilateria;Deuterostoma;Chordata;Vertebrata;Mammalia;Primates;Hominidae; Homo sapiens
- Short gene description: Caspase-9 Precursor (CASP-9)(EC 3.4.22.62)(ICE-like apoptotic protease 6)(ICE-LAP6)(Apoptotic protease Mch-6)(Apoptotic protease-activating factor 3)(APAF-3) [Contains Caspase-9 subunit p35;Caspase-9 subunit p10] [Source:UniProtKB/Swiss-Prot;Acc:P55211]
- Family: Caspase
- Process: apoptosis,
- Pathways: intrinsic pathway,
- Criteria: manually curated
- Curator comment: Caspase-9 is the binding partner of Apaf-1, becoming activated upon binding to the latter in response to mitochondrial cytochrome c efflux. Apaf-1 and caspase-9 form a holoenzyme (called the apoptosome) which is comprised of seven molecules of Apaf-1 and possibly a similar number of caspase-9 molecules (although the precise number of caspase-9 molecules within the apoptosome may be as low as 1 or 2). Upon activation within the apoptosome, caspase-9 then directly processes and activates caspases -3 and -7 downstream. Other than caspases -3 and -7, few other substrates for caspase-9 are known.
- Mouse ortholog(s): Casp9
- WIKI: CASP9-H_sapiens
References [+]
- The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32.
- Srinivasula SM, Fernandes-Alnemri T, Zangrilli J, Robertson N, Armstrong RC, Wang L, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES
- Recent evidence suggests that CPP32 is an essential component of an aspartate-specific cysteine protease (ASCP) cascade responsible for apoptosis execution in mammalian cells. Activation of CPP32 could lead to activation of other downstream ASCPs, resulting in late morphological changes such as lamin cleavage and DNA fragmentation, observed in cells undergoing apoptosis. Here we describe the identification and cloning of a novel human ASCP named Mch6 from Jurkat T lymphocytes. We demonstrate that the pro-enzymes of Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for mature CPP32. Site-directed mutagenesis revealed that CPP32 processes pro-Mch6 preferentially at Asp330 to generate two subunits of molecular masses 37 kDa (p37) and 10 kDa (p10). However, CPP32 processes pro-Mch2alpha at three aspartate processing sites (Asp23, Asp179, and Asp193) to produce the large (p18) and small (p11) subunits of the mature Mch2alpha enzyme. The CPP32-processed Mch2alpha is capable of cleaving the VEIDN lamin cleavage site, indicating that CPP32 can, in fact, activate pro-Mch2alpha. Granzyme B at a concentration that allows processing and activation of CPP32 failed to process pro-Mch2alpha. However, incubation of pro-Mch2alpha with granzyme B in the presence of a cellular extract containing pro-CPP32 resulted in activation of pro-CPP32 and subsequent processing of pro-Mch2alpha. Interestingly, granzyme B can also process pro-Mch6 but at a site N-terminal to that cleaved by CPP32. These data suggest that Mch2alpha and Mch6 are downstream proteases activated in CPP32- and granzyme B-mediated apoptosis. This is the first demonstration of a protease cascade involving granzyme B, CPP32, Mch2alpha, and Mch6 and evidence that the lamin-cleaving enzyme Mch2 is a target of mature CPP32. J Biol Chem. 1996 Oct 25;271(43):27099-106.
- References from Mouse ortholog(s):
- Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.
- Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA
- Caspases are essential components of the mammalian cell death machinery. Here we test the hypothesis that Caspase 9 (Casp9) is a critical upstream activator of caspases through gene targeting in mice. The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development. Casp9 deletion prevents activation of Casp3 in embryonic brains in vivo, and Casp9-deficient thymocytes show resistance to a subset of apoptotic stimuli, including absence of Casp3-like cleavage and delayed DNA fragmentation. Moreover, the cytochrome c-mediated cleavage of Casp3 is absent in the cytosolic extracts of Casp9-deficient cells but is restored after addition of in vitro-translated Casp9. Together, these results indicate that Casp9 is a critical upstream activator of the caspase cascade in vivo. Cell. 1998 Aug 7;94(3):325-37.
- Differential requirement for caspase 9 in apoptotic pathways in vivo.
- Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW
- Mutation of Caspase 9 (Casp9) results in embryonic lethality and defective brain development associated with decreased apoptosis. Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation. Casp9-/- thymocytes are also resistant to dexamethasone- and gamma irradiation-induced apoptosis, but are surprisingly sensitive to apoptosis induced by UV irradiation or anti-CD95. Resistance to apoptosis is accompanied by retention of the mitochondrial membrane potential in mutant cells. In addition, cytochrome c is translocated to the cytosol of Casp9-/- ES cells upon UV stimulation, suggesting that Casp9 acts downstream of cytochrome c. Caspase processing is inhibited in Casp9-/- ES cells but not in thymocytes or splenocytes. Comparison of the requirement for Casp9 and Casp3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells. Cell. 1998 Aug 7;94(3):339-52.
Structure & Sequence [+]
Pfam domains:
(Pfam is a large collection of protein families.)
| Source | Domain Name | Start | End |
|---|---|---|---|
| PFAM A | CARD | 41 | 127 |
| PFAM A | Peptidase_C14 | 196 | 436 |
Protein sequence [+]
CASP9 | Homo sapiens | 9606 | length:456
RGGRPWGGGGSWGLGRAAEARKRTEAAWSLSWLLAMDEADRRLLRRCRLRLVEELQVDQL
WDALLSRELFRPHMIEDIQRAGSGSRRDQARQLIIDLETRGSQALPLFISCLEDTGQDML
ASFLRTNRQAAKLSKPTLENLTPVVLRPEIRKPEVLRPETPRPVDIGSGGFGDVGALESL
RGNADLAYILSMEPCGHCLIINNVNFCRESGLRTRTGSNIDCEKLRRRFSSLHFMVEVKG
DLTAKKMVLALLELAQQDHGALDCCVVVILSHGCQASHLQFPGAVYGTDGCPVSVEKIVN
IFNGTSCPSLGGKPKLFFIQACGGEQKDHGFEVASTSPEDESPGSNPEPDATPFQEGLRT
FDQLDAISSLPTPSDIFVSYSTFPGFVSWRDPKSGSWYVETLDDIFEQWAHSEDLQSLLL
RVSAAFLCKGEGRLLRGSVSSWGWGFGVSRAGPNQG
WDALLSRELFRPHMIEDIQRAGSGSRRDQARQLIIDLETRGSQALPLFISCLEDTGQDML
ASFLRTNRQAAKLSKPTLENLTPVVLRPEIRKPEVLRPETPRPVDIGSGGFGDVGALESL
RGNADLAYILSMEPCGHCLIINNVNFCRESGLRTRTGSNIDCEKLRRRFSSLHFMVEVKG
DLTAKKMVLALLELAQQDHGALDCCVVVILSHGCQASHLQFPGAVYGTDGCPVSVEKIVN
IFNGTSCPSLGGKPKLFFIQACGGEQKDHGFEVASTSPEDESPGSNPEPDATPFQEGLRT
FDQLDAISSLPTPSDIFVSYSTFPGFVSWRDPKSGSWYVETLDDIFEQWAHSEDLQSLLL
RVSAAFLCKGEGRLLRGSVSSWGWGFGVSRAGPNQG
Structure links:
- Smartdomain prediction information: SM00114
- Smartdomain prediction information: SM00115
- Prosite motif and domain information: PS01121
- Prosite motif and domain information: PS01122
- Profile motif and domain profile information: PS50209
- Profile motif and domain profile information: PS50208
- Profile motif and domain profile information: PS50207
- Interpro domain information: P55211
- PFAM domain and domain family information: P55211
Evolution [+]
View protein alignment and tree with Jalview:
Explore tree at phylomeDB: Click here.
Homologs list [+]
| Name | Relationship | Species |
|---|---|---|
| Q90WU0_CHICK | orthology | Chicken |
| CASP9 | orthology | Chimpanzee |
| IPI00704513.4 | orthology | Cow |
| Q45T68_CANFA | orthology | Dog |
| CASP9 | orthology | Fugu |
| CASP9 | orthology | Gasterosteus |
| CASP9 | orthology | Gorilla |
| CASP9 | orthology | Horse |
| CASP9 | orthology | Lyzard |
| CASP9 | orthology | Macaca |
| CASP9 | orthology | Medaka |
| CASP9 | orthology | Monodelphis |
| Casp9 | orthology | Mouse |
| CASP9 | orthology | Orangutan |
| CASP9 | orthology | Ornithorhynchus |
| CASP9 | orthology | Rabbit |
| Casp9 | orthology | Rat |
| CASP9 | orthology | Tetraodon |
| CASP9 | orthology | Xenopus |
| CASP9 | orthology | Zebra finch |
| D_rerio_ENSDARP00000047019 | orthology | Zebrafish |
| A_aegypti_AAEL003444-PA | paralogy | Aedes |
| A_aegypti_AAEL014348-PA | paralogy | Aedes |
| A_aegypti_AAEL011562-PA | paralogy | Aedes |
| CASPS6 | paralogy | Anopheles |
| CASPS5 | paralogy | Anopheles |
| CASPS7 | paralogy | Anopheles |
| CASPS3 | paralogy | Anopheles |
| CASPS8 | paralogy | Anopheles |
| CASPL2 | paralogy | Anopheles |
| CASPS4 | paralogy | Anopheles |
| NP_990056.1 | paralogy | Chicken |
| NP_001038154.1 | paralogy | Chicken |
| NP_989923.1 | paralogy | Chicken |
| CASP2_CHICK | paralogy | Chicken |
| CASP7 | paralogy | Chicken |
| NP_990057.1 | paralogy | Chicken |
| CASP3_PANTR | paralogy | Chimpanzee |
| XR_025516.1 | paralogy | Chimpanzee |
| CASP8 | paralogy | Chimpanzee |
| CASP7 | paralogy | Chimpanzee |
| CASP2 | paralogy | Chimpanzee |
| C_intestinalis_ENSCINP00000024485 | paralogy | Ciona |
| C_intestinalis_ENSCINP00000003204 | paralogy | Ciona |
| IPI00689801.3 | paralogy | Cow |
| NP_001039435.1 | paralogy | Cow |
| CASP6_BOVIN | paralogy | Cow |
| CASP3_BOVIN | paralogy | Cow |
| IPI00707783.1 | paralogy | Cow |
| Q38JA9_CANFA | paralogy | Dog |
| CASP10 | paralogy | Dog |
| CASP7 | paralogy | Dog |
| CASP3_CANFA | paralogy | Dog |
| CASP2 | paralogy | Dog |
| Dcp-1 | paralogy | Fly |
| Ice | paralogy | Fly |
| CASP7 | paralogy | Fugu |
| NP_001027871.1 | paralogy | Fugu |
| T_rubripes_ENSTRUP00000044662 | paralogy | Fugu |
| CASP2 | paralogy | Fugu |
| T_rubripes_ENSTRUP00000024467 | paralogy | Fugu |
| CASP6 | paralogy | Fugu |
| CASP7 | paralogy | Gasterosteus |
| CASP3 (2 of 4) | paralogy | Gasterosteus |
| CASP2 | paralogy | Gasterosteus |
| CASP3 (1 of 4) | paralogy | Gasterosteus |
| CASP6 | paralogy | Gasterosteus |
| CASP3 (4 of 4) | paralogy | Gasterosteus |
| G_aculeatus_ENSGACP00000005791 | paralogy | Gasterosteus |
| CASP3 (3 of 4) | paralogy | Gasterosteus |
| CASP8 | paralogy | Gorilla |
| CASP7 | paralogy | Gorilla |
| Q3S2Z5_HORSE | paralogy | Horse |
| CASP7 | paralogy | Horse |
| CASP2 | paralogy | Horse |
| CASP8 | paralogy | Horse |
| CASP10 | paralogy | Horse |
| CASP6 | paralogy | Horse |
| CASP10 | paralogy | Human |
| CASP8 | paralogy | Human |
| CASP3 | paralogy | Human |
| CASP7 | paralogy | Human |
| CASP6 | paralogy | Human |
| CASP2 | paralogy | Human |
| CASP10 | paralogy | Lyzard |
| CASP3 | paralogy | Lyzard |
| CASP2 | paralogy | Lyzard |
| CASP7 | paralogy | Lyzard |
| CASP7 | paralogy | Macaca |
| CASP10 | paralogy | Macaca |
| CASP8 | paralogy | Macaca |
| Q8SPP8_MACMU | paralogy | Macaca |
| Q8SPU2_MACMU | paralogy | Macaca |
| CASP2 | paralogy | Medaka |
| CASP7 | paralogy | Medaka |
| Q8JIS8_ORYLA | paralogy | Medaka |
| Q8JIS9_ORYLA | paralogy | Medaka |
| NP_001033061.1 | paralogy | Monodelphis |
| CASP2 | paralogy | Monodelphis |
| NP_001033059.1 | paralogy | Monodelphis |
| CASP8 | paralogy | Monodelphis |
| Casp3 | paralogy | Mouse |
| Casp8 | paralogy | Mouse |
| Casp7 | paralogy | Mouse |
| Casp6 | paralogy | Mouse |
| Casp2 | paralogy | Mouse |
| Q5RCR7_PONPY | paralogy | Orangutan |
| CASP3 | paralogy | Orangutan |
| CASP7 | paralogy | Orangutan |
| CASP2 | paralogy | Orangutan |
| CASP6 | paralogy | Orangutan |
| CASP6 | paralogy | Ornithorhynchus |
| CASP7 | paralogy | Ornithorhynchus |
| CASP8 | paralogy | Ornithorhynchus |
| CASP2 | paralogy | Ornithorhynchus |
| CASP3 | paralogy | Ornithorhynchus |
| O_anatinus_ENSOANP00000019254 | paralogy | Ornithorhynchus |
| CASP2 | paralogy | Rabbit |
| CASP10 | paralogy | Rabbit |
| CASP7 | paralogy | Rabbit |
| CASP8 | paralogy | Rabbit |
| Casp3 | paralogy | Rat |
| Casp7 | paralogy | Rat |
| Casp2 | paralogy | Rat |
| Casp8 | paralogy | Rat |
| T_nigroviridis_ENSTNIP00000001216 | paralogy | Tetraodon |
| CASP2 | paralogy | Tetraodon |
| CASP6 | paralogy | Tetraodon |
| CASP7 | paralogy | Tetraodon |
| CASP3 | paralogy | Tetraodon |
| T_nigroviridis_ENSTNIP00000010722 | paralogy | Tetraodon |
| ced-3 | paralogy | Worm |
| CASP2 | paralogy | Xenopus |
| CASP3 | paralogy | Xenopus |
| casp7 | paralogy | Xenopus |
| T_guttata_ENSTGUP00000004278 | paralogy | Zebra finch |
| CASP8 | paralogy | Zebra finch |
| CASP3 | paralogy | Zebra finch |
| T_guttata_ENSTGUP00000011206 | paralogy | Zebra finch |
| T_guttata_ENSTGUP00000013612 | paralogy | Zebra finch |
| casp3a | paralogy | Zebrafish |
| casp8l2 | paralogy | Zebrafish |
| NP_001077331.1 | paralogy | Zebrafish |
| LOC100000522 | paralogy | Zebrafish |
| casp8l1 | paralogy | Zebrafish |
| casp2 | paralogy | Zebrafish |
| A2BGE2_DANRE | paralogy | Zebrafish |
| casp7 | paralogy | Zebrafish |
| casp3b | paralogy | Zebrafish |
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Gene Ontology [+]
| GO id | Name | Ontology type | Evidence |
|---|---|---|---|
| GO:0006508 | proteolysis | biological_proccess | IEA |
| GO:0042981 | regulation of apoptosis | biological_proccess | IEA |
| GO:0006915 | apoptosis | biological_proccess | IEA |
| GO:0006974 | response to DNA damage stimulus | biological_proccess | IEA |
| GO:0006919 | activation of caspase activity | biological_proccess | IEA |
| GO:0043525 | positive regulation of neuron apoptosis | biological_proccess | IEA |
| GO:0009411 | response to UV | biological_proccess | IEA |
| GO:0006917 | induction of apoptosis | biological_proccess | IEA |
| GO:0008635 | activation of caspase activity by cytochrome c | biological_proccess | TAS |
| GO:0004197 | cysteine-type endopeptidase activity | mollecular_function | IEA |
| GO:0005515 | protein binding | mollecular_function | IEA |
| GO:0008234 | cysteine-type peptidase activity | mollecular_function | IEA |
| GO:0042277 | peptide binding | mollecular_function | IEA |
| GO:0008047 | enzyme activator activity | mollecular_function | TAS |
| GO:0004197 | cysteine-type endopeptidase activity | mollecular_function | TAS |
| GO:0008233 | peptidase activity | mollecular_function | IEA |
| GO:0005515 | protein binding | mollecular_function | IPI |
| GO:0005622 | intracellular | cell_component | IEA |
| GO:0005634 | nucleus | cell_component | IEA |
| GO:0005829 | cytosol | cell_component | IEA |
| GO:0005625 | soluble fraction | cell_component | IEA |
| GO:0005737 | cytoplasm | cell_component | IEA |
| GO:0005829 | cytosol | cell_component | EXP |
Check GO Evidence Codes here
miRNAs [+]
| miRNA | Regulation | Description | Pubmed |
|---|---|---|---|
| hsa-miR-133a | overexpression by mature miRNA transfection | Co-transfection of the chimeric constructs with miR-1 or miR-133 (Fig. 5) into HEK293 cells, consistently resulted in smaller luciferase activity relative to transfection of the chimeric plasmid alone. | Ref. |
| hsa-miR-133a | overexpression by mature miRNA transfection | Co-transfection of the chimeric constructs with miR-1 or miR-133 (Fig. 5) into HEK293 cells, consistently resulted in smaller luciferase activity relative to transfection of the chimeric plasmid alone. | Ref. |
| hsa-miR-133a | overexpression by mature miRNA transfection | Co-transfection of the chimeric constructs with miR-1 or miR-133 (Fig. 5) into HEK293 cells, consistently resulted in smaller luciferase activity relative to transfection of the chimeric plasmid alone. | Ref. |
| hsa-miR-133a | overexpression by mature miRNA transfection | Co-transfection of the chimeric constructs with miR-1 or miR-133 (Fig. 5) into HEK293 cells, consistently resulted in smaller luciferase activity relative to transfection of the chimeric plasmid alone. | Ref. |
| hsa-miR-133a | overexpression by mature miRNA transfection | Co-transfection of the chimeric constructs with miR-1 or miR-133 (Fig. 5) into HEK293 cells, consistently resulted in smaller luciferase activity relative to transfection of the chimeric plasmid alone. | Ref. |
| hsa-miR-133a | downregulation by antisense miRNA oligonucleotide | Co-application of miR-1 or miR-133 with their respective AMOs eliminated the silencing effects. | Ref. |
| hsa-miR-133a | downregulation by antisense miRNA oligonucleotide | Co-application of miR-1 or miR-133 with their respective AMOs eliminated the silencing effects. | Ref. |
| hsa-miR-133a | downregulation by antisense miRNA oligonucleotide | Co-application of miR-1 or miR-133 with their respective AMOs eliminated the silencing effects. | Ref. |
| hsa-miR-133a | downregulation by antisense miRNA oligonucleotide | Co-application of miR-1 or miR-133 with their respective AMOs eliminated the silencing effects. | Ref. |
| hsa-miR-133a | downregulation by antisense miRNA oligonucleotide | Co-application of miR-1 or miR-133 with their respective AMOs eliminated the silencing effects. | Ref. |
Curated Isoforms [+]
Info from The Vertebrate Genome Annotation (VEGA) database.
(*) Canonical transcript and translation forms.
Information from other databases [+]
- Gene info from HGNC [?] :1511
- Gene related info from GeneCards [?] : CASP9
- Ensembl genome browser [?] : ENSG00000132906
- Expression info from Arrayexpress [?] : ENSG00000132906
- Protein expression from Protein Atlas: [?] ENSG00000132906
- Community gene edition from Wikigenes: [?] 842
- OMIM gene information: 602234
- OMIM disease information:
Click on [?] for more information.
