CAST Gene

Name	calpastatin
Description	The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Calpastatin (CAST) is the endogenous, highly specific inhibitor of calpains – the calcium‐activated cysteine proteases that modulate diverse cellular processes. In many tissues, CAST acts as a critical gatekeeper by restricting calpain‐mediated proteolysis of key substrates. In neurons, for example, increased CAST expression or activity limits calpain‐driven cleavage of cytoskeletal and mitochondrial proteins, thereby protecting against excitotoxicity, abnormal tau fragmentation, and prion propagation; these protective effects have been demonstrated in models of acute neuronal injury and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In skeletal muscle, CAST regulates calpain activity during both development and disuse, thereby reducing aberrant proteolysis that contributes to atrophy and sarcopenia. Overexpression of CAST in muscle preserves myofibrillar integrity and prevents shifts in myosin isoforms associated with atrophy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Similarly, in the cardiovascular system, CAST modulates pathological remodeling. In models of angiotensin II–induced hypertension and diabetic cardiomyopathy, increased CAST expression blunts calpain‐mediated degradation of proteins essential for focal adhesion turnover, energy metabolism, and ion transport, thereby limiting hypertrophy, inflammation, and apoptotic loss of cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In immune cells such as neutrophils, CAST prevents over‐activation of calpain‐1, thereby regulating pro‐apoptotic cleavage events that determine cell lifespan and ensuring balanced inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In addition, CAST influences intracellular signaling pathways—for instance, by controlling the degradation of β–catenin and other regulatory proteins—thereby impacting cell adhesion and proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic studies indicate that CAST variants may contribute to interindividual differences in therapeutic responses, such as to interferon‐β in multiple sclerosis, highlighting its potential as a pharmacogenomic marker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Finally, in prion disease models, inhibition of calpain by CAST reduces the formation of pathogenic protein fragments, underscoring its broad relevance in protecting cellular proteostasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", while deficits in lysosomal function that lead to calpain overactivation further implicate CAST in maintaining overall protein turnover and cell viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies demonstrate that CAST serves as a central regulator of calpain activity across multiple organ systems, coordinating processes as varied as apoptosis, cytoskeletal remodeling, metabolism, and inflammation. Its modulation—either by genetic variation or through experimental overexpression—can shift cellular outcomes from degeneration toward survival, making CAST a promising target for therapeutic intervention in diverse pathologic conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Makoto Higuchi, Masanori Tomioka, Jiro Takano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct mechanistic roles of calpain and caspase activation in neurodegeneration as revealed in mice overexpressing their specific inhibitors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M500939200"}], "href": "https://doi.org/10.1074/jbc.M500939200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15699033"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15699033"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Arezu Jahani-Asl, Karine Pilon-Larose, William Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The mitochondrial inner membrane GTPase, optic atrophy 1 (Opa1), restores mitochondrial morphology and promotes neuronal survival following excitotoxicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.167155"}], "href": "https://doi.org/10.1074/jbc.M110.167155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21041314"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21041314"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Bin Liang, Bao-Yu Duan, Xiu-Ping Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain activation promotes BACE1 expression, amyloid precursor protein processing, and amyloid plaque formation in a transgenic mouse model of Alzheimer disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.117960"}], "href": "https://doi.org/10.1074/jbc.M110.117960"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20595388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20595388"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mala V Rao, Mary Kate McBrayer, Jabbar Campbell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Specific calpain inhibition by calpastatin prevents tauopathy and neurodegeneration and restores normal lifespan in tau P301L mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.1132-14.2014"}], "href": "https://doi.org/10.1523/JNEUROSCI.1132-14.2014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25009256"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25009256"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "James G Tidball, Melissa J Spencer "}, {"type": "b", "children": [{"type": "t", "text": "Expression of a calpastatin transgene slows muscle wasting and obviates changes in myosin isoform expression during murine muscle disuse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2002.024935"}], "href": "https://doi.org/10.1113/jphysiol.2002.024935"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12482888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12482888"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Giuseppina Samengo, Anna Avik, Brian Fedor, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Age-related loss of nitric oxide synthase in skeletal muscle causes reductions in calpain S-nitrosylation that increase myofibril degradation and sarcopenia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging Cell (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/acel.12003"}], "href": "https://doi.org/10.1111/acel.12003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22950758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22950758"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Emmanuel Letavernier, Joëlle Perez, Agnès Bellocq, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting the calpain/calpastatin system as a new strategy to prevent cardiovascular remodeling in angiotensin II-induced hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.107.160077"}], "href": "https://doi.org/10.1161/CIRCRESAHA.107.160077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18258859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18258859"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ying Li, Yanwen Li, Qingping Feng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/cvr/cvp189"}], "href": "https://doi.org/10.1093/cvr/cvp189"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19505932"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19505932"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Anita S Galvez, Abhinav Diwan, Amy M Odley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardiomyocyte degeneration with calpain deficiency reveals a critical role in protein homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.RES.0000261938.28365.11"}], "href": "https://doi.org/10.1161/01.RES.0000261938.28365.11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17332428"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17332428"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Frank Altznauer, Sébastien Conus, Andrea Cavalli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-1 regulates Bax and subsequent Smac-dependent caspase-3 activation in neutrophil apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M308576200"}], "href": "https://doi.org/10.1074/jbc.M308576200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14612448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14612448"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Roberta Benetti, Tamara Copetti, Stefania Dell'Orso, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The calpain system is involved in the constitutive regulation of beta-catenin signaling functions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501810200"}], "href": "https://doi.org/10.1074/jbc.M501810200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15817486"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15817486"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Esther Byun, Stacy J Caillier, Xavier Montalban, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arch Neurol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1001/archneurol.2008.47"}], "href": "https://doi.org/10.1001/archneurol.2008.47"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18195134"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18195134"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Rajgopal Yadavalli, Rodney P Guttmann, Tanya Seward, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calpain-dependent endoproteolytic cleavage of PrPSc modulates scrapie prion propagation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M400793200"}], "href": "https://doi.org/10.1074/jbc.M400793200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15026410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15026410"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "MaryKate McBrayer, Ralph A Nixon "}, {"type": "b", "children": [{"type": "t", "text": "Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST20130201"}], "href": "https://doi.org/10.1042/BST20130201"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24256243"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24256243"}]}]}]}
Synonyms	PLACK, BS-17
Proteins	ICAL_HUMAN
NCBI Gene ID	831
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CAST has 8,888 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 111 datasets.

Click the + buttons to view associations for CAST from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CAST Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAST gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAST gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CAST gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CAST gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CAST gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving CAST protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CAST gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CAST gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CAST gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CAST gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CAST gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CAST protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CAST gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAST gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CAST gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CAST gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CAST gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CAST protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CAST protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CAST protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CAST gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CAST gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CAST gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with CAST gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CAST gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving CAST gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with CAST gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CAST gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CAST gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CAST gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CAST gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CAST gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for CAST protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CAST gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CAST gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CAST gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CAST from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CAST gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with CAST gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CAST gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.