Details for: CASP9

Gene ID: 842

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CASP9

Ensembl ID: ENSG00000132906

Description: caspase 9

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 7.47
    rCSI 9.02%
    PRS 98.04
  • VIP GABAergic cortical interneuron CL4023016
    CSI 5.95
    rCSI 7.11%
    PRS 88.15
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 3.58
    rCSI 4.45%
    PRS 86.32
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 3.28
    rCSI 2.52%
    PRS 97.64
  • colon epithelial cell CL0011108
    CSI 2.92
    rCSI 3.06%
    PRS 94.03
  • myeloid leukocyte CL0000766
    CSI 2.89
    rCSI 2.66%
    PRS 96.68
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.72
    rCSI 6.09%
    PRS 88.44
  • BEST4+ enteroycte CL4030026
    CSI 2.71
    rCSI 3.38%
    PRS 94.9
  • Mueller cell CL0000636
    CSI 2.69
    rCSI 6.13%
    PRS 91.86
  • vascular leptomeningeal cell CL4023051
    CSI 2.66
    rCSI 4.67%
    PRS 93.92
  • ependymal cell CL0000065
    CSI 2.57
    rCSI 5.21%
    PRS 82.95
  • lung ciliated cell CL1000271
    CSI 2.48
    rCSI 2.87%
    PRS 92
  • ciliated epithelial cell CL0000067
    CSI 2.48
    rCSI 2.18%
    PRS 89.75
  • pancreatic acinar cell CL0002064
    CSI 2.43
    rCSI 3.24%
    PRS 96.78
  • intermediate monocyte CL0002393
    CSI 2.37
    rCSI 3.57%
    PRS 97.97
  • multi-ciliated epithelial cell CL0005012
    CSI 2.27
    rCSI 2.26%
    PRS 91.75
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.12
    rCSI 2.73%
    PRS 89.02
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 2.05
    rCSI 3.43%
    PRS 88.18
  • renal principal cell CL0005009
    CSI 2.02
    rCSI 5.25%
    PRS 94.94
  • vascular associated smooth muscle cell CL0000359
    CSI 1.99
    rCSI 6.44%
    PRS 94.86
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 1.86
    rCSI 3.28%
    PRS 87.68
  • inhibitory interneuron CL0000498
    CSI 1.65
    rCSI 3.8%
    PRS 89.99
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.63
    rCSI 3.71%
    PRS 90.06
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.43
    rCSI 3.63%
    PRS 92.39
  • podocyte CL0000653
    CSI 1.4
    rCSI 6.21%
    PRS 95.59
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.32
    rCSI 3.55%
    PRS 96.38
  • parietal epithelial cell CL1000452
    CSI 1.07
    rCSI 2.87%
    PRS 92.74
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 0.97
    rCSI 2.37%
    PRS 86.38
  • dopaminergic neuron CL0000700
    CSI 0.86
    rCSI 4.88%
    PRS 88.56
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.79
    rCSI 2.85%
    PRS 86.57
  • medium spiny neuron CL1001474
    CSI 0.4
    rCSI 3.45%
    PRS 90.51

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [CASP9](/details-gene/842) (Caspase-9) is a protein-coding gene located on chromosome 1p36.21 that encodes a critical member of the cysteine-aspartic acid protease (caspase) family. As a key initiator caspase, [CASP9](/details-gene/842) plays a central role in the intrinsic pathway of apoptosis, or programmed cell death. It is activated within a large protein complex known as the apoptosome, which forms in response to intracellular stress signals such as DNA damage. Its expression is significant across a wide variety of cell types, including immune cells like the [CD1c-positive myeloid dendritic cell](/details-cell/CL0002399) and neuronal subtypes such as the [VIP GABAergic cortical interneuron](/details-cell/CL4023016), indicating its fundamental importance in tissue homeostasis and stress response throughout the body. Clinical association with OMIM entry [602234](https://omim.org/entry/602234) underscores its relevance to human health and disease. ## Cellular Roles and Expression Landscape The expression profile of [CASP9](/details-gene/842) highlights its role as a ubiquitous yet finely regulated component of the cellular apoptotic machinery. **Overall**, the gene shows the highest significance in specialized immune and neuronal cell types. Its top CSI score is observed in [CD1c-positive myeloid dendritic cell](/details-cell/CL0002399) (CSI: 7.47), suggesting a crucial function in regulating the lifespan and turnover of these key antigen-presenting cells. High significance is also noted in other myeloid lineage cells, including [CD14-low, CD16-positive monocyte](/details-cell/CL0002396) and [intermediate monocyte](/details-cell/CL0002393), consistent with its annotated role in the [leukocyte apoptotic process](/details-cell/GO:0071887). A second prominent functional context for [CASP9](/details-gene/842) is the central nervous system. It demonstrates high significance in specific inhibitory interneuron populations, including [VIP GABAergic cortical interneuron](/details-cell/CL4023016) and [pvalb GABAergic cortical interneuron](/details-cell/CL4023018), as well as in glial cells like [astrocyte of the cerebral cortex](/details-cell/CL0002605). This pattern suggests that [CASP9](/details-gene/842)-mediated apoptosis is a key process in neural development, circuit refinement, and the response to neurotoxic insults. The gene's broad expression in diverse epithelial cells, such as [colon epithelial cell](/details-cell/CL0011108), [lung ciliated cell](/details-cell/CL1000271), and [pancreatic acinar cell](/details-cell/CL0002064), further reinforces its fundamental role in maintaining tissue integrity and eliminating damaged or unwanted cells across multiple organ systems. ## Pathways and Molecular Function Functionally, [CASP9](/details-gene/842) is an initiator caspase with [cysteine-type endopeptidase activity involved in apoptotic process](/details-cell/GO:0097153). Its primary mechanism of action is within the [Intrinsic pathway for apoptosis](/details-cell/R-HSA-109606). Upon cellular stress, such as DNA damage ([GO:0006974](https://www.ebi.ac.uk/QuickGO/term/GO:0006974)), cytochrome c is released from the [mitochondrion](/details-cell/GO:0005739) into the [cytosol](/details-cell/GO:0005829). There, it binds to the scaffold protein APAF1, triggering the assembly of the [apoptosome](/details-cell/GO:0043293) ([R-HSA-111458](https://reactome.org/content/detail/R-HSA-111458)). [CASP9](/details-gene/842) is recruited to this complex, where it undergoes dimerization and auto-proteolytic activation ([R-HSA-111459](https://reactome.org/content/detail/R-HSA-111459)). Once activated, [CASP9](/details-gene/842) cleaves and activates downstream effector caspases, such as caspase-3 and caspase-7, thereby executing the final stages of cell death. The activity of [CASP9](/details-gene/842) is tightly regulated. For instance, research indicates it can be inhibited via phosphorylation by the ERK MAPK pathway ([Link](https://doi.org/10.1038/ncb1005)) or by direct binding of proteins like HAX-1 ([Link](https://doi.org/10.1161/01.res.0000237387.05259.a5)). Furthermore, splice variants of [CASP9](/details-gene/842) have been identified that lack the catalytic domain and can act as endogenous dominant-negative inhibitors of apoptosis ([Link](https://pubmed.ncbi.nlm.nih.gov/10070954/), [Link](https://doi.org/10.1074/jbc.274.4.2072)), adding another layer of regulatory complexity. ## Research Directions The widespread yet cell-type-specific significance of [CASP9](/details-gene/842) provides a foundation for several compelling research avenues. **Proposed Hypotheses:** 1. The high significance of [CASP9](/details-gene/842) in distinct neuronal subtypes, such as [VIP GABAergic cortical interneuron](/details-cell/CL4023016), suggests that these cells may have a lower threshold for initiating apoptosis in response to metabolic or excitotoxic stress. We hypothesize that age-related decline in cellular stress response pathways leads to inappropriate [CASP9](/details-gene/842) activation in these specific interneurons, contributing to the circuit dysfunction seen in early-stage neurodegenerative diseases. 2. Given its top rank in [CD1c-positive myeloid dendritic cell](/details-cell/CL0002399), [CASP9](/details-gene/842) likely plays a critical role in determining the lifespan of these cells after antigen presentation. We hypothesize that selective inhibition of [CASP9](/details-gene/842) in dendritic cells could prolong their survival, thereby enhancing the duration and strength of T-cell priming and improving the efficacy of vaccines or immunotherapies. **Experimental Approach:** To test the second hypothesis regarding dendritic cell lifespan, a conditional knockout mouse model could be employed. [CASP9](/details-gene/842) could be specifically deleted in dendritic cells using a Cre-lox system driven by a DC-specific promoter (e.g., CD11c-Cre). These knockout mice and wild-type controls would be immunized with a model antigen. The persistence and activation status of antigen-loaded dendritic cells in the draining lymph nodes would be quantified over time using flow cytometry. Concurrently, the magnitude and quality of the antigen-specific T cell response would be assessed by measuring T cell proliferation, cytokine production (e.g., IFN-gamma), and the formation of memory T cell populations. An increased number of surviving dendritic cells and a more robust T cell response in the knockout mice would support the hypothesis. **Therapeutic Potential:** [CASP9](/details-gene/842) represents a dual-faceted therapeutic target. In oncology, where apoptosis is often suppressed, small-molecule activators of the apoptosome or direct [CASP9](/details-gene/842) activators could restore programmed cell death in cancer cells. Conversely, in diseases characterized by excessive cell loss, such as neurodegeneration, myocardial infarction, or stroke, inhibitors of [CASP9](/details-gene/842) could be cytoprotective. The gene's broad expression profile poses a major challenge, as systemic modulation would likely cause significant side effects. Therefore, therapeutic strategies would require highly targeted delivery systems (e.g., antibody-drug conjugates, lipid nanoparticles) or the development of drugs that selectively modulate [CASP9](/details-gene/842) activity in a disease-specific context.

Genular Protein ID: 1978674921

Symbol: CASP9_HUMAN

Name: Caspase-9

UniProtKB Accession Codes:

P55211 B4E1A3 O95348 Q53Y70 Q5JRU9 Q5UGI1 Q92852 Q9BQ62 Q9UEQ3 Q9UIJ8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CDD 2 CORUM 1 CTD 1 ChEMBL 1 ComplexPortal 2 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 1 EC 1 ELM 1 EMBL 16 EMDB 2 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 39 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MEROPS 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 10 PDBsum 10 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 5 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 Pumba 1 RNAct 1 Reactome 9 RefSeq 4 SABIO-RK 1 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 8663294

Title: ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B.

PubMed ID: 8663294

DOI: 10.1074/jbc.271.28.16720

PubMed ID: 8900201

Title: The Ced-3/interleukin 1beta converting enzyme-like homolog Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for the apoptotic mediator CPP32.

PubMed ID: 8900201

DOI: 10.1074/jbc.271.43.27099

PubMed ID: 10384055

Title: Genomic organization of the human caspase-9 gene on chromosome 1p36.1-p36.3.

PubMed ID: 10384055

DOI: 10.1007/s003359901086

PubMed ID: 10070954

Title: Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis.

PubMed ID: 10070954

PubMed ID: 9890966

Title: A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis.

PubMed ID: 9890966

DOI: 10.1074/jbc.274.4.2072

PubMed ID: 16780893

Title: Cloning of a novel human caspase-9 splice variant containing only the CARD domain.

PubMed ID: 16780893

DOI: 10.1016/j.lfs.2006.04.026

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 12792650

Title: Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK.

PubMed ID: 12792650

DOI: 10.1038/ncb1005

PubMed ID: 15200957

Title: Dual role of BRUCE as an antiapoptotic IAP and a chimeric E2/E3 ubiquitin ligase.

PubMed ID: 15200957

DOI: 10.1016/j.molcel.2004.05.018

PubMed ID: 15657060

Title: c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage.

PubMed ID: 15657060

DOI: 10.1074/jbc.m413787200

PubMed ID: 16857965

Title: Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition.

PubMed ID: 16857965

DOI: 10.1161/01.res.0000237387.05259.a5

PubMed ID: 16352606

Title: Caspase-7 is directly activated by the approximately 700-kDa apoptosome complex and is released as a stable XIAP-caspase-7 approximately 200-kDa complex.

PubMed ID: 16352606

DOI: 10.1074/jbc.m507393200

PubMed ID: 16916640

Title: Engineered hybrid dimers: tracking the activation pathway of caspase-7.

PubMed ID: 16916640

DOI: 10.1016/j.molcel.2006.06.020

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 19255499

Title: HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death.

PubMed ID: 19255499

DOI: 10.1159/000204088

PubMed ID: 19118655

Title: Comparative proteomics analysis of caspase-9-protein complexes in untreated and cytochrome c/dATP stimulated lysates of NSCLC cells.

PubMed ID: 19118655

DOI: 10.1016/j.jprot.2008.11.016

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 27889207

Title: Dual site phosphorylation of caspase-7 by PAK2 blocks apoptotic activity by two distinct mechanisms.

PubMed ID: 27889207

DOI: 10.1016/j.str.2016.11.001

PubMed ID: 35446120

Title: Calmodulin binding activates chromobacterium CopC effector to ADP-riboxanate host apoptotic caspases.

PubMed ID: 35446120

DOI: 10.1128/mbio.00690-22

PubMed ID: 35338844

Title: Pathogen hijacks programmed cell death signaling by arginine ADPR-deacylization of caspases.

PubMed ID: 35338844

DOI: 10.1016/j.molcel.2022.03.010

PubMed ID: 36758106

Title: Structural basis for SMAC-mediated antagonism of caspase inhibition by the giant ubiquitin ligase BIRC6.

PubMed ID: 36758106

DOI: 10.1126/science.ade8840

PubMed ID: 36758105

Title: Structural basis for regulation of apoptosis and autophagy by the BIRC6/SMAC complex.

PubMed ID: 36758105

DOI: 10.1126/science.ade8873

PubMed ID: 11734640

Title: Dimer formation drives the activation of the cell death protease caspase 9.

PubMed ID: 11734640

DOI: 10.1073/pnas.231465798

PubMed ID: 12620238

Title: Mechanism of XIAP-mediated inhibition of caspase-9.

PubMed ID: 12620238

DOI: 10.1016/s1097-2765(03)00054-6

PubMed ID: 23516580

Title: The E. coli effector protein NleF is a caspase inhibitor.

PubMed ID: 23516580

DOI: 10.1371/journal.pone.0058937

Sequence Information:

  • Length: 416
  • Mass: 46281
  • Checksum: 78E0180DF2A3BDD2
  • Sequence:
    • 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

Genular Protein ID: 2218277359

Symbol: F8VVS7_HUMAN

Name: N/A

UniProtKB Accession Codes:

F8VVS7

Database IDs:

ARBA 6 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID-ORCS 1 CDD 2 CTD 1 DNASU 1 DisGeNET 1 EMBL 1 Ensembl 2 ExpressionAtlas 1 GO 5 Gene3D 2 GeneTree 1 HGNC 1 InterPro 10 MassIVE 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PIRSF 1 PIRSR 1 PRINTS 1 PROSITE 8 PeptideAtlas 2 Pfam 2 PhylomeDB 1 Proteomes 2 ProteomicsDB 2 RefSeq 1 RuleBase 1 SAM 1 SMART 2 SMR 1 SUPFAM 2 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

Sequence Information:

  • Length: 421
  • Mass: 46453
  • Checksum: 6B5EC6A06494125F
  • Sequence:
    • 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 QSLLLRVSAA FLCKGEGRLL RGSVSSWGWG FGVSRAGPNQ 
G