CASP9 (Caspase 9): Apoptosis Initiator and Therapeutic Target
A comprehensive biomedical overview of the CASP9 gene, its protein function, associated diseases, expression patterns, mutations, and molecular pathways.
Gene Information Card
| Symbol | CASP9 |
|---|---|
| Full Name | Caspase 9 |
| Gene Type | Protein-coding |
| Chromosomal Location | 1p36.21 |
| NCBI Gene ID | 842 ncbi.nlm.nih.gov/gene/842 |
| Ensembl ID | ENSG00000132906 |
| UniProt ID | P55211 |
| OMIM ID | 602234 |
| HGNC ID | 1511 |
| Aliases | APAF-3, APAF3, ICE-LAP6, MCH6, PPP1R56 |
Description
CASP9 encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspase 9 is an initiator caspase that plays a central role in the intrinsic (mitochondrial) apoptosis pathway. Upon apoptotic stimuli, cytochrome c is released from mitochondria and binds to apoptotic protease-activating factor 1 (APAF1), forming the apoptosome complex, which recruits and activates pro-caspase 9. Activated caspase 9 then cleaves and activates downstream effector caspases (e.g., CASP3, CASP7), leading to cellular disassembly. CASP9 is also involved in other processes such as cell differentiation, immune response, and inflammation. Mutations and dysregulation of CASP9 have been implicated in various cancers and developmental disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (various types) | Reduced expression or loss-of-function mutations in CASP9 impair apoptosis, promoting tumorigenesis and resistance to chemotherapy. | COSMIC; ClinVar; multiple studies (e.g., PMID: 15696205) |
| Non-Hodgkin lymphoma | Somatic mutations and decreased expression of CASP9 contribute to apoptosis evasion in lymphoma cells. | COSMIC; ClinVar; PMID: 14504080 |
| Gastric cancer | Hypermethylation of the CASP9 promoter leads to reduced expression, associated with poor prognosis. | PMID: 18566567 |
| Colorectal cancer | Loss of CASP9 expression correlates with advanced stage and metastasis. | PMID: 16951327 |
| Autoimmune lymphoproliferative syndrome (ALPS) type II | Germline mutations in CASP9 impair apoptosis of lymphocytes, leading to lymphoproliferation and autoimmunity. | OMIM; PMID: 10521306 |
| Developmental delay and intellectual disability | Biallelic loss-of-function mutations in CASP9 cause a neurodevelopmental disorder with seizures and brain abnormalities. | OMIM; PMID: 28111015 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.4 | Medium |
| Heart | 8.2 | Low |
| Liver | 6.5 | Low |
| Kidney | 7.8 | Low |
| Lung | 5.9 | Low |
| Spleen | 10.1 | Medium |
| Testis | 9.3 | Low |
| Colon | 6.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 8.5 | Moderate expression |
| MCF7 (breast cancer) | 7.2 | Low expression |
| A549 (lung cancer) | 6.9 | Low expression |
| K562 (leukemia) | 9.8 | Moderate expression |
| HepG2 (liver cancer) | 7.5 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.287C>T (p.Pro96Leu) | Missense | Rare (0.01%) | Impairs caspase 9 activity, reduces apoptosis |
| c.472G>A (p.Asp158Asn) | Missense | Rare (0.005%) | Decreased catalytic activity |
| c.758A>G (p.Gln253Arg) | Missense | Rare (0.02%) | Alters substrate binding |
| c.1-?_*?del (whole gene deletion) | Copy number loss | Very rare | Loss of function, haploinsufficiency |
| c.532C>T (p.Arg178Ter) | Nonsense | Rare (0.001%) | Truncated protein, loss of function |
Mutation functional classification
Loss of Function (LOF)
Most CASP9 mutations in cancer and ALPS are loss-of-function, reducing apoptosis and promoting cell survival.
Gain of Function (GOF)
Gain-of-function mutations are rare; some somatic variants may increase activity but are not well characterized.
Dominant Negative (DN)
Certain missense mutations can act as dominant-negative by forming inactive heterodimers with wild-type caspase 9.
View complete mutation data：
Gene Ontology (GO)
| • cysteine-type endopeptidase activity | • cysteine-type peptidase activity |
| • protein homodimerization activity | • identical protein binding |
| • apoptotic process | • intrinsic apoptotic signaling pathway |
| • activation of cysteine-type endopeptidase activity involved in apoptotic process | • proteolysis |
| • regulation of apoptotic process | • mitochondrial outer membrane permeabilization |
| • apoptosome complex | • cytosol |
| • nucleus |
Pathways
• Intrinsic Apoptosis Pathway
• Apoptosome-mediated caspase activation
• p53-dependent apoptosis
• Cytochrome c-mediated signaling
• Caspase cascade in apoptosis
Protein Summary
Caspase 9 is a 416-amino acid protein (UniProt P55211) with a prodomain containing a caspase recruitment domain (CARD) that mediates interaction with APAF1. It is synthesized as an inactive zymogen and undergoes proteolytic cleavage at Asp315 and Asp330 to produce large and small subunits that form the active heterotetramer. Caspase 9 is a key initiator of the intrinsic apoptosis pathway, activated by the apoptosome. It also has non-apoptotic roles in cell differentiation and immune regulation. Post-translational modifications include phosphorylation (e.g., at Thr125, Ser196) that modulate its activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CASP9 Knockout HEK293 Cell Line | EDJ-KQ183 | Human | 842 | Details Get a Quote |
| CASP9 Knockout HeLa Cell Line | EDJ-KQ18347 | Human | 842 | Details Get a Quote |
| CASP9 Knockout A-549 Cell Line | EDJ-KQ19454 | Human | 842 | Details Get a Quote |
| CASP9 Knockout HCT 116 Cell Line | EDJ-KQ19455 | Human | 842 | Details Get a Quote |
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