CASP9_HUMAN
ID CASP9_HUMAN Reviewed; 416 AA.
AC P55211; B4E1A3; O95348; Q53Y70; Q5JRU9; Q5UGI1; Q92852; Q9BQ62; Q9UEQ3;
AC Q9UIJ8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 22-FEB-2003, sequence version 3.
DT 03-AUG-2022, entry version 232.
DE RecName: Full=Caspase-9;
DE Short=CASP-9;
DE EC=3.4.22.62 {ECO:0000269|PubMed:23516580};
DE AltName: Full=Apoptotic protease Mch-6;
DE AltName: Full=Apoptotic protease-activating factor 3;
DE Short=APAF-3;
DE AltName: Full=ICE-like apoptotic protease 6;
DE Short=ICE-LAP6;
DE Contains:
DE RecName: Full=Caspase-9 subunit p35;
DE Contains:
DE RecName: Full=Caspase-9 subunit p10;
DE Flags: Precursor;
GN Name=CASP9; Synonyms=MCH6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS VAL-28 AND ARG-221.
RX PubMed=8663294; DOI=10.1074/jbc.271.28.16720;
RA Duan H., Orth K., Chinnaiyan A.M., Poirier G.G., Froelich C.J., He W.-W.,
RA Dixit V.M.;
RT "ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the
RT cytotoxic T cell protease granzyme B.";
RL J. Biol. Chem. 271:16720-16724(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEOLYTIC PROCESSING.
RC TISSUE=T-cell;
RX PubMed=8900201; DOI=10.1074/jbc.271.43.27099;
RA Srinivasula S.M., Fernandes-Alnemri T., Zangrilli J., Robertson N.,
RA Armstrong R.C., Wang L., Trapani J.A., Tomaselli K.J., Litwack G.,
RA Alnemri E.S.;
RT "The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the
RT lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator
RT CPP32.";
RL J. Biol. Chem. 271:27099-27106(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=10384055; DOI=10.1007/s003359901086;
RA Hadano S., Nasir J., Nichol K., Rasper D.M., Vaillancourt J.P.,
RA Sherer S.W., Beatty B.G., Ikeda J.E., Nicholson D.W., Hayden M.R.;
RT "Genomic organization of the human caspase-9 gene on chromosome 1p36.1-
RT p36.3.";
RL Mamm. Genome 10:757-760(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=10070954;
RA Srinivasula S.M., Ahmad M., Guo Y., Zhan Y., Lazebnik Y.,
RA Fernandes-Alnemri T., Alnemri E.S.;
RT "Identification of an endogenous dominant-negative short isoform of
RT caspase-9 that can regulate apoptosis.";
RL Cancer Res. 59:999-1002(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Stomach cancer;
RA Izawa M., Mori T., Ito H., Sairenji T.;
RT "Molecular cloning and sequencing of a cDNA predicting an alternative form
RT of pro-caspase-9 from human gastric cancer cell lines.";
RL Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RA Miho Y., Momoi T., Fujita E.;
RT "A novel splicing product of human caspase-9 lacking protease activity.";
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT VAL-28.
RX PubMed=9890966; DOI=10.1074/jbc.274.4.2072;
RA Seol D.W., Billiar T.R.;
RT "A caspase-9 variant missing the catalytic site is an endogenous inhibitor
RT of apoptosis.";
RL J. Biol. Chem. 274:2072-2076(1999).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND VARIANT VAL-28.
RX PubMed=16780893; DOI=10.1016/j.lfs.2006.04.026;
RA Wang P., Shi T., Ma D.;
RT "Cloning of a novel human caspase-9 splice variant containing only the CARD
RT domain.";
RL Life Sci. 79:934-940(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS VAL-28; LEU-99; ILE-102;
RP VAL-106; ASP-114; HIS-173 AND ARG-221.
RG NIEHS SNPs program;
RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Kidney;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Eye, and Lymph;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP PHOSPHORYLATION AT THR-125.
RX PubMed=12792650; DOI=10.1038/ncb1005;
RA Allan L.A., Morrice N., Brady S., Magee G., Pathak S., Clarke P.R.;
RT "Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK.";
RL Nat. Cell Biol. 5:647-654(2003).
RN [16]
RP INTERACTION WITH BIRC6/BRUCE.
RX PubMed=15200957; DOI=10.1016/j.molcel.2004.05.018;
RA Bartke T., Pohl C., Pyrowolakis G., Jentsch S.;
RT "Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin
RT ligase.";
RL Mol. Cell 14:801-811(2004).
RN [17]
RP FUNCTION IN APOPTOSIS, INTERACTION WITH ABL1, PROTEOLYTIC PROCESSING,
RP PHOSPHORYLATION AT TYR-153 BY ABL1, AND MUTAGENESIS OF TYR-153.
RX PubMed=15657060; DOI=10.1074/jbc.m413787200;
RA Raina D., Pandey P., Ahmad R., Bharti A., Ren J., Kharbanda S.,
RA Weichselbaum R., Kufe D.;
RT "c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic
RT response to DNA damage.";
RL J. Biol. Chem. 280:11147-11151(2005).
RN [18]
RP INTERACTION WITH HAX1, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=16857965; DOI=10.1161/01.res.0000237387.05259.a5;
RA Han Y., Chen Y.S., Liu Z., Bodyak N., Rigor D., Bisping E., Pu W.T.,
RA Kang P.M.;
RT "Overexpression of HAX-1 protects cardiac myocytes from apoptosis through
RT caspase-9 inhibition.";
RL Circ. Res. 99:415-423(2006).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-125; SER-302 AND SER-307, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [20]
RP INTERACTION WITH BCL2L10.
RX PubMed=19255499; DOI=10.1159/000204088;
RA Kim J.H., Yoon S., Won M., Sim S.H., Ko J.J., Han S., Lee K.A., Lee K.,
RA Bae J.;
RT "HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-
RT dependent cell death.";
RL Cell. Physiol. Biochem. 23:43-52(2009).
RN [21]
RP INTERACTION WITH EFHD2.
RX PubMed=19118655; DOI=10.1016/j.jprot.2008.11.016;
RA Checinska A., Giaccone G., Rodriguez J.A., Kruyt F.A.E., Jimenez C.R.;
RT "Comparative proteomics analysis of caspase-9-protein complexes in
RT untreated and cytochrome c/dATP stimulated lysates of NSCLC cells.";
RL J. Proteomics 72:575-585(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-307, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-310, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 140-416, AND SUBUNIT.
RX PubMed=11734640; DOI=10.1073/pnas.231465798;
RA Renatus M., Stennicke H.R., Scott F.L., Liddington R.C., Salvesen G.S.;
RT "Dimer formation drives the activation of the cell death protease caspase
RT 9.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:14250-14255(2001).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 140-416 IN COMPLEX WITH
RP BIRC4/XIAP.
RX PubMed=12620238; DOI=10.1016/s1097-2765(03)00054-6;
RA Shiozaki E.N., Chai J., Rigotti D.J., Riedl S.J., Li P., Srinivasula S.M.,
RA Alnemri E.S., Fairman R., Shi Y.;
RT "Mechanism of XIAP-mediated inhibition of caspase-9.";
RL Mol. Cell 11:519-527(2003).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (3.49 ANGSTROMS) OF 140-416 IN COMPLEX WITH E.COLI
RP NLEF, INTERACTION WITH E.COLI NLEF, SUBUNIT, CATALYTIC ACTIVITY, FUNCTION,
RP AND ACTIVITY REGULATION.
RX PubMed=23516580; DOI=10.1371/journal.pone.0058937;
RA Blasche S., Mortl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA Lavrik I., Gronewold T.M., Maskos K., Donnenberg M.S., Ullmann D., Uetz P.,
RA Kogl M.;
RT "The E. coli effector protein NleF is a caspase inhibitor.";
RL PLoS ONE 8:E58937-E58937(2013).
CC -!- FUNCTION: Involved in the activation cascade of caspases responsible
CC for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to
CC activation of the protease which then cleaves and activates caspase-3.
CC Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner.
CC Proteolytically cleaves poly(ADP-ribose) polymerase (PARP).
CC -!- FUNCTION: Isoform 2 lacks activity is an dominant-negative inhibitor of
CC caspase-9.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for an Asp residue at position P1 and with
CC a marked preference for His at position P2. It has a preferred
CC cleavage sequence of Leu-Gly-His-Asp-|-Xaa.; EC=3.4.22.62;
CC Evidence={ECO:0000269|PubMed:23516580};
CC -!- ACTIVITY REGULATION: Inhibited by the effector protein NleF that is
CC produced by pathogenic E.coli; this inhibits apoptosis.
CC {ECO:0000269|PubMed:23516580}.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10)
CC subunit. Caspase-9 and APAF1 bind to each other via their respective
CC NH2-terminal CED-3 homologous domains in the presence of cytochrome C
CC and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1.
CC Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce
CC and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction
CC is direct and increases in the response of cells to genotoxic stress
CC and ABL1/c-Abl activation. Interacts with BCL2L10 (PubMed:19255499).
CC Interacts with NleF from pathogenic E.coli.
CC {ECO:0000269|PubMed:11734640, ECO:0000269|PubMed:12620238,
CC ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:15657060,
CC ECO:0000269|PubMed:16857965, ECO:0000269|PubMed:19118655,
CC ECO:0000269|PubMed:19255499, ECO:0000269|PubMed:23516580}.
CC -!- INTERACTION:
CC P55211; O14727: APAF1; NbExp=22; IntAct=EBI-516799, EBI-446492;
CC P55211; Q13490: BIRC2; NbExp=12; IntAct=EBI-516799, EBI-514538;
CC P55211; Q96CA5: BIRC7; NbExp=12; IntAct=EBI-516799, EBI-517623;
CC P55211; Q6PIA0: BIRC8; NbExp=3; IntAct=EBI-516799, EBI-2129837;
CC P55211; P42574: CASP3; NbExp=2; IntAct=EBI-516799, EBI-524064;
CC P55211; P43146: DCC; NbExp=2; IntAct=EBI-516799, EBI-1222919;
CC P55211; Q13418: ILK; NbExp=2; IntAct=EBI-516799, EBI-747644;
CC P55211; P98170: XIAP; NbExp=23; IntAct=EBI-516799, EBI-517127;
CC P55211; Q8XAL7: nleF; Xeno; NbExp=6; IntAct=EBI-516799, EBI-10039292;
CC P55211-1; P55211-1: CASP9; NbExp=3; IntAct=EBI-15553290, EBI-15553290;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=9L, Alpha;
CC IsoId=P55211-1; Sequence=Displayed;
CC Name=2; Synonyms=9S, Beta;
CC IsoId=P55211-2; Sequence=VSP_000818;
CC Name=3; Synonyms=Gamma;
CC IsoId=P55211-3; Sequence=VSP_043910, VSP_043911;
CC Name=4;
CC IsoId=P55211-4; Sequence=VSP_044256;
CC -!- TISSUE SPECIFICITY: Ubiquitous, with highest expression in the heart,
CC moderate expression in liver, skeletal muscle, and pancreas. Low levels
CC in all other tissues. Within the heart, specifically expressed in
CC myocytes. {ECO:0000269|PubMed:16857965}.
CC -!- DEVELOPMENTAL STAGE: Expressed at low levels in fetal heart, at
CC moderate levels in neonate heart, and at high levels in adult heart.
CC {ECO:0000269|PubMed:16857965}.
CC -!- PTM: Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3
CC generate the two active subunits. Caspase-8 and -10 can also be
CC involved in these processing events.
CC -!- PTM: Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-
CC 125 is sufficient to block caspase-9 processing and subsequent caspase-
CC 3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the
CC response of cells to DNA damage. {ECO:0000269|PubMed:12792650,
CC ECO:0000269|PubMed:15657060}.
CC -!- MISCELLANEOUS: [Isoform 3]: May function as an endogenous apoptotic
CC inhibitor, inhibits the BAX-mediated cleavage of procaspase-3.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CASP9ID423ch1p36.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp9/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Caspase-9 entry;
CC URL="https://en.wikipedia.org/wiki/Caspase-9";
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DR EMBL; U56390; AAC50640.1; -; mRNA.
DR EMBL; U60521; AAC50776.1; -; mRNA.
DR EMBL; AB019205; BAA82697.1; -; Genomic_DNA.
DR EMBL; AF093130; AAD12248.1; -; mRNA.
DR EMBL; AB015653; BAA78780.1; -; mRNA.
DR EMBL; AB020979; BAA87905.1; -; mRNA.
DR EMBL; AF110376; AAD13615.1; -; mRNA.
DR EMBL; AY732490; AAV33129.1; -; mRNA.
DR EMBL; AY214168; AAO21133.1; -; Genomic_DNA.
DR EMBL; BT006911; AAP35557.1; -; mRNA.
DR EMBL; AK303743; BAG64715.1; -; mRNA.
DR EMBL; AL512883; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471167; EAW51730.1; -; Genomic_DNA.
DR EMBL; CH471167; EAW51731.1; -; Genomic_DNA.
DR EMBL; BC002452; AAH02452.1; -; mRNA.
DR EMBL; BC006463; AAH06463.1; -; mRNA.
DR CCDS; CCDS158.1; -. [P55211-1]
DR CCDS; CCDS159.2; -. [P55211-4]
DR CCDS; CCDS59995.1; -. [P55211-2]
DR PIR; G02635; G02635.
DR RefSeq; NP_001220.2; NM_001229.4. [P55211-1]
DR RefSeq; NP_001264983.1; NM_001278054.1. [P55211-2]
DR RefSeq; NP_127463.2; NM_032996.3. [P55211-4]
DR RefSeq; XP_005246071.1; XM_005246014.2. [P55211-4]
DR PDB; 1JXQ; X-ray; 2.80 A; A/B/C/D=140-416.
DR PDB; 1NW9; X-ray; 2.40 A; B=140-416.
DR PDB; 2AR9; X-ray; 2.80 A; A/B/C/D=139-416.
DR PDB; 3D9T; X-ray; 1.50 A; C/D=316-321.
DR PDB; 3V3K; X-ray; 3.49 A; A/C/E/G/I/K/M/O=141-416.
DR PDB; 3YGS; X-ray; 2.50 A; P=1-95.
DR PDB; 4RHW; X-ray; 2.10 A; E/F=1-100.
DR PDB; 5JUY; EM; 4.10 A; O/P/Q/R=1-95.
DR PDB; 5WVC; X-ray; 2.99 A; B/D/F=1-128.
DR PDB; 5WVE; EM; 4.40 A; S/T/U/V/Y=1-100.
DR PDBsum; 1JXQ; -.
DR PDBsum; 1NW9; -.
DR PDBsum; 2AR9; -.
DR PDBsum; 3D9T; -.
DR PDBsum; 3V3K; -.
DR PDBsum; 3YGS; -.
DR PDBsum; 4RHW; -.
DR PDBsum; 5JUY; -.
DR PDBsum; 5WVC; -.
DR PDBsum; 5WVE; -.
DR AlphaFoldDB; P55211; -.
DR SMR; P55211; -.
DR BioGRID; 107292; 58.
DR ComplexPortal; CPX-3762; Apoptosome.
DR ComplexPortal; CPX-991; Caspase-9 complex.
DR CORUM; P55211; -.
DR DIP; DIP-27625N; -.
DR ELM; P55211; -.
DR IntAct; P55211; 31.
DR MINT; P55211; -.
DR STRING; 9606.ENSP00000330237; -.
DR BindingDB; P55211; -.
DR ChEMBL; CHEMBL2273; -.
DR DrugBank; DB00282; Pamidronic acid.
DR GuidetoPHARMACOLOGY; 1625; -.
DR MEROPS; C14.010; -.
DR GlyGen; P55211; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P55211; -.
DR PhosphoSitePlus; P55211; -.
DR BioMuta; CASP9; -.
DR DMDM; 28558771; -.
DR EPD; P55211; -.
DR jPOST; P55211; -.
DR MassIVE; P55211; -.
DR MaxQB; P55211; -.
DR PaxDb; P55211; -.
DR PeptideAtlas; P55211; -.
DR PRIDE; P55211; -.
DR ProteomicsDB; 56814; -. [P55211-1]
DR ProteomicsDB; 56815; -. [P55211-2]
DR ProteomicsDB; 56816; -. [P55211-3]
DR ProteomicsDB; 5741; -.
DR Antibodypedia; 749; 1874 antibodies from 50 providers.
DR DNASU; 842; -.
DR Ensembl; ENST00000333868.10; ENSP00000330237.5; ENSG00000132906.18. [P55211-1]
DR Ensembl; ENST00000348549.9; ENSP00000255256.7; ENSG00000132906.18. [P55211-2]
DR Ensembl; ENST00000375890.8; ENSP00000365051.4; ENSG00000132906.18. [P55211-4]
DR GeneID; 842; -.
DR KEGG; hsa:842; -.
DR MANE-Select; ENST00000333868.10; ENSP00000330237.5; NM_001229.5; NP_001220.2.
DR UCSC; uc001awn.5; human. [P55211-1]
DR CTD; 842; -.
DR DisGeNET; 842; -.
DR GeneCards; CASP9; -.
DR HGNC; HGNC:1511; CASP9.
DR HPA; ENSG00000132906; Low tissue specificity.
DR MIM; 602234; gene.
DR neXtProt; NX_P55211; -.
DR OpenTargets; ENSG00000132906; -.
DR PharmGKB; PA26094; -.
DR VEuPathDB; HostDB:ENSG00000132906; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000159698; -.
DR HOGENOM; CLU_036904_5_0_1; -.
DR InParanoid; P55211; -.
DR OMA; RYKQIPG; -.
DR PhylomeDB; P55211; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.62; 2681.
DR PathwayCommons; P55211; -.
DR Reactome; R-HSA-111458; Formation of apoptosome.
DR Reactome; R-HSA-111459; Activation of caspases through apoptosome-mediated cleavage.
DR Reactome; R-HSA-111463; SMAC (DIABLO) binds to IAPs.
DR Reactome; R-HSA-111464; SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-198323; AKT phosphorylates targets in the cytosol.
DR Reactome; R-HSA-418889; Caspase activation via Dependence Receptors in the absence of ligand.
DR Reactome; R-HSA-5674400; Constitutive Signaling by AKT1 E17K in Cancer.
DR Reactome; R-HSA-9627069; Regulation of the apoptosome activity.
DR SABIO-RK; P55211; -.
DR SignaLink; P55211; -.
DR SIGNOR; P55211; -.
DR BioGRID-ORCS; 842; 14 hits in 1084 CRISPR screens.
DR EvolutionaryTrace; P55211; -.
DR GeneWiki; Caspase-9; -.
DR GenomeRNAi; 842; -.
DR Pharos; P55211; Tchem.
DR PRO; PR:P55211; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P55211; protein.
DR Bgee; ENSG00000132906; Expressed in adrenal tissue and 202 other tissues.
DR ExpressionAtlas; P55211; baseline and differential.
DR Genevisible; P55211; HS.
DR GO; GO:0043293; C:apoptosome; IDA:UniProtKB.
DR GO; GO:0008303; C:caspase complex; IPI:ComplexPortal.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central.
DR GO; GO:0008047; F:enzyme activator activity; TAS:ProtInc.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0008233; F:peptidase activity; IDA:BHF-UCL.
DR GO; GO:0019901; F:protein kinase binding; IDA:UniProtKB.
DR GO; GO:0017124; F:SH3 domain binding; IDA:UniProtKB.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IDA:ComplexPortal.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0008635; P:activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c; IDA:ComplexPortal.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IMP:UniProtKB.
DR GO; GO:0071549; P:cellular response to dexamethasone stimulus; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
DR GO; GO:1904019; P:epithelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0044346; P:fibroblast apoptotic process; IEA:Ensembl.
DR GO; GO:0034349; P:glial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IC:ComplexPortal.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IMP:UniProtKB.
DR GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR GO; GO:0071887; P:leukocyte apoptotic process; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0030220; P:platelet formation; TAS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:ComplexPortal.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:2001020; P:regulation of response to DNA damage stimulus; IMP:UniProtKB.
DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR GO; GO:0032025; P:response to cobalt ion; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0042770; P:signal transduction in response to DNA damage; IDA:UniProtKB.
DR CDD; cd08326; CARD_CASP9; 1.
DR CDD; cd00032; CASc; 1.
DR DisProt; DP02860; -.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR042147; CARD_CASP9.
DR InterPro; IPR033171; Caspase-9.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR033139; Caspase_cys_AS.
DR InterPro; IPR016129; Caspase_his_AS.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR PANTHER; PTHR10454:SF157; PTHR10454:SF157; 1.
DR Pfam; PF00619; CARD; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00114; CARD; 1.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Hydrolase; Phosphoprotein;
KW Protease; Reference proteome; Thiol protease; Zymogen.
FT PROPEP 1..?
FT /evidence="ECO:0000255"
FT /id="PRO_0000004640"
FT CHAIN ?..315
FT /note="Caspase-9 subunit p35"
FT /id="PRO_0000004641"
FT PROPEP 316..330
FT /id="PRO_0000004642"
FT CHAIN 331..416
FT /note="Caspase-9 subunit p10"
FT /id="PRO_0000004643"
FT DOMAIN 1..92
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 294..320
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 237
FT /evidence="ECO:0000250"
FT ACT_SITE 287
FT /evidence="ECO:0000250"
FT MOD_RES 125
FT /note="Phosphothreonine; by MAPK1"
FT /evidence="ECO:0000269|PubMed:12792650,
FT ECO:0007744|PubMed:18669648"
FT MOD_RES 153
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000269|PubMed:15657060"
FT MOD_RES 302
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 307
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 310
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..83
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_044256"
FT VAR_SEQ 140..289
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:10070954,
FT ECO:0000303|PubMed:9890966, ECO:0000303|Ref.5,
FT ECO:0000303|Ref.6"
FT /id="VSP_000818"
FT VAR_SEQ 152..154
FT /note="AYI -> TVL (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16780893"
FT /id="VSP_043910"
FT VAR_SEQ 155..416
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16780893"
FT /id="VSP_043911"
FT VARIANT 28
FT /note="A -> V (in dbSNP:rs1052571)"
FT /evidence="ECO:0000269|PubMed:16780893,
FT ECO:0000269|PubMed:8663294, ECO:0000269|PubMed:9890966,
FT ECO:0000269|Ref.9"
FT /id="VAR_015415"
FT VARIANT 99
FT /note="S -> L (in dbSNP:rs4646008)"
FT /evidence="ECO:0000269|Ref.9"
FT /id="VAR_015416"
FT VARIANT 102
FT /note="T -> I (in dbSNP:rs2308941)"
FT /evidence="ECO:0000269|Ref.9"
FT /id="VAR_015417"
FT VARIANT 106
FT /note="L -> V (in dbSNP:rs2308938)"
FT /evidence="ECO:0000269|Ref.9"
FT /id="VAR_015418"
FT VARIANT 114
FT /note="E -> D (in dbSNP:rs2020897)"
FT /evidence="ECO:0000269|Ref.9"
FT /id="VAR_015419"
FT VARIANT 136
FT /note="F -> L (in dbSNP:rs1132312)"
FT /id="VAR_059198"
FT VARIANT 173
FT /note="R -> H (in dbSNP:rs2308950)"
FT /evidence="ECO:0000269|Ref.9"
FT /id="VAR_015420"
FT VARIANT 176
FT /note="G -> R (in dbSNP:rs2308949)"
FT /id="VAR_016131"
FT VARIANT 185
FT /note="I -> M (in dbSNP:rs9282624)"
FT /id="VAR_022053"
FT VARIANT 192
FT /note="R -> C (in dbSNP:rs2308939)"
FT /id="VAR_016132"
FT VARIANT 221
FT /note="Q -> R (in dbSNP:rs1052576)"
FT /evidence="ECO:0000269|PubMed:8663294, ECO:0000269|Ref.9"
FT /id="VAR_015421"
FT MUTAGEN 153
FT /note="Y->F: Inhibits tyrosine phosphorylation. Reduces
FT caspase-9 subunit p35 formation in response to genotoxic
FT stress. Attenuates ABL1/c-Abl-mediated caspase-3
FT activation, DNA fragmentation and UV irradiation-induced
FT apoptosis."
FT /evidence="ECO:0000269|PubMed:15657060"
FT CONFLICT 32
FT /note="R -> S (in Ref. 2; AAC50776, 3; BAA82697 and 6;
FT BAA87905)"
FT /evidence="ECO:0000305"
FT CONFLICT 96
FT /note="A -> G (in Ref. 1; AAC50640)"
FT /evidence="ECO:0000305"
FT CONFLICT 197
FT /note="L -> P (in Ref. 2; AAC50776 and 3; BAA82697)"
FT /evidence="ECO:0000305"
FT HELIX 3..11
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 13..19
FT /evidence="ECO:0007829|PDB:4RHW"
FT TURN 23..25
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 26..31
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 37..44
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 51..62
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 69..79
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 83..93
FT /evidence="ECO:0007829|PDB:4RHW"
FT HELIX 143..147
FT /evidence="ECO:0007829|PDB:1NW9"
FT TURN 149..151
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:1JXQ"
FT STRAND 161..167
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 173..175
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 183..196
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 199..206
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 209..221
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 224..226
FT /evidence="ECO:0007829|PDB:2AR9"
FT STRAND 228..239
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 244..246
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 249..251
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 257..259
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 260..265
FT /evidence="ECO:0007829|PDB:1NW9"
FT TURN 269..271
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 273..275
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 280..287
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 317..319
FT /evidence="ECO:0007829|PDB:3D9T"
FT STRAND 340..346
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 351..353
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 354..356
FT /evidence="ECO:0007829|PDB:3V3K"
FT TURN 357..359
FT /evidence="ECO:0007829|PDB:1JXQ"
FT HELIX 362..374
FT /evidence="ECO:0007829|PDB:1NW9"
FT TURN 375..377
FT /evidence="ECO:0007829|PDB:1NW9"
FT HELIX 380..392
FT /evidence="ECO:0007829|PDB:1NW9"
FT STRAND 395..398
FT /evidence="ECO:0007829|PDB:1JXQ"
FT STRAND 402..406
FT /evidence="ECO:0007829|PDB:1JXQ"
FT STRAND 408..410
FT /evidence="ECO:0007829|PDB:1NW9"
SQ SEQUENCE 416 AA; 46281 MW; 78E0180DF2A3BDD2 CRC64;
MDEADRRLLR RCRLRLVEEL QVDQLWDALL SRELFRPHMI EDIQRAGSGS RRDQARQLII
DLETRGSQAL PLFISCLEDT GQDMLASFLR TNRQAAKLSK PTLENLTPVV LRPEIRKPEV
LRPETPRPVD IGSGGFGDVG ALESLRGNAD LAYILSMEPC GHCLIINNVN FCRESGLRTR
TGSNIDCEKL RRRFSSLHFM VEVKGDLTAK KMVLALLELA QQDHGALDCC VVVILSHGCQ
ASHLQFPGAV YGTDGCPVSV EKIVNIFNGT SCPSLGGKPK LFFIQACGGE QKDHGFEVAS
TSPEDESPGS NPEPDATPFQ EGLRTFDQLD AISSLPTPSD IFVSYSTFPG FVSWRDPKSG
SWYVETLDDI FEQWAHSEDL QSLLLRVANA VSVKGIYKQM PGCFNFLRKK LFFKTS
