CRELD2 Gene

Name	cysteine-rich with EGF-like domains 2
Description	Predicted to enable calcium ion binding activity and protein disulfide isomerase activity. Predicted to be located in Golgi apparatus; endoplasmic reticulum; and extracellular space. [provided by Alliance of Genome Resources, Mar 2025]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CRELD2 is a multifunctional, evolutionarily conserved glycoprotein that is strongly induced by endoplasmic reticulum (ER) stress and plays diverse roles in cellular proteostasis. Its expression is activated via a conserved ER stress response element (ERSE) in its promoter, regulated by ATF6 and NF‐Y, which leads to rapid induction upon exposure to ER stressors such as thapsigargin, tunicamycin, and brefeldin A."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Functionally, CRELD2 exhibits protein disulphide isomerase (PDI)–like activity that assists in the folding and processing of misfolded or mutant proteins; for example, its interaction with mutant matrilin‐3 in models of multiple epiphyseal dysplasia occurs in a genotype‐specific manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, CRELD2 participates in key differentiation processes by modulating signaling pathways—for instance, it is directly up‐regulated by BMP9 and potentiates osteogenic differentiation of mesenchymal stem cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and it has been implicated in the regulation of receptor trafficking, such as that of the α4β2 nicotinic acetylcholine receptor."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, the trafficking and secretion of CRELD2 are tightly regulated by components of the ER–Golgi machinery – notably by Sar1 and GRP78 – so that under certain conditions of perturbed vesicular acidification its secretion is markedly enhanced."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Beyond its intracellular chaperone functions, secreted CRELD2 appears to contribute to paracrine signaling in the tumor microenvironment and may serve as a biomarker linking ER stress to pathological conditions such as hepatic steatosis, kidney disease, and cancer progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore that CRELD2 functions as an adaptive mediator of the ER stress response – facilitating proper protein folding through its PDI‐like activity, modulating differentiation and survival pathways in diverse tissues (including cartilage and bone), and contributing to extracellular signaling under pathophysiological conditions. Its dynamic regulation and multifunctional roles make CRELD2 a promising target for therapeutic intervention in a range of ER stress–associated diseases.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kentaro Oh-hashi, Hisashi Koga, Shun Ikeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRELD2 is a novel endoplasmic reticulum stress-inducible gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2009.07.047"}], "href": "https://doi.org/10.1016/j.bbrc.2009.07.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19615339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19615339"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kentaro Oh-Hashi, Hisashi Koga, Shun Ikeda, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of an ER stress response element in regulating the bidirectional promoter of the mouse CRELD2 - ALG12 gene pair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Genomics (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2164-11-664"}], "href": "https://doi.org/10.1186/1471-2164-11-664"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21106106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21106106"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kentaro Oh-Hashi, Tomomi Tejima, Yoko Hirata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the 5'-flanking region of the mouse asparagine-linked glycosylation 12 homolog gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Biol Lett (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2478/s11658-013-0091-2"}], "href": "https://doi.org/10.2478/s11658-013-0091-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23818223"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23818223"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Claire L Hartley, Sarah Edwards, Lorna Mullan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddt383"}], "href": "https://doi.org/10.1093/hmg/ddt383"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23956175"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23956175"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "José A Ortiz, Mar Castillo, Eduardo Dominguez del Toro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The cysteine-rich with EGF-like domains 2 (CRELD2) protein interacts with the large cytoplasmic domain of human neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunits."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2005.03473.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2005.03473.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16238698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16238698"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jiye Zhang, Yaguang Weng, Xing Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endoplasmic reticulum (ER) stress inducible factor cysteine-rich with EGF-like domains 2 (Creld2) is an important mediator of BMP9-regulated osteogenic differentiation of mesenchymal stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0073086"}], "href": "https://doi.org/10.1371/journal.pone.0073086"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24019898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24019898"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Ella P Dennis, Sarah M Edwards, Robert M Jackson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRELD2 Is a Novel LRP1 Chaperone That Regulates Noncanonical WNT Signaling in Skeletal Development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.4010"}], "href": "https://doi.org/10.1002/jbmr.4010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32181934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32181934"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kentaro Oh-hashi, Yoshiro Kanamori, Yoko Hirata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of V-ATPase inhibitor-induced secretion of cysteine-rich with EGF-like domains 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Biol Toxicol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10565-014-9274-5"}], "href": "https://doi.org/10.1007/s10565-014-9274-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24687431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24687431"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Kentaro Oh-hashi, Ryosuke Kunieda, Yoko Hirata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biosynthesis and secretion of mouse cysteine-rich with EGF-like domains 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2011.06.029"}], "href": "https://doi.org/10.1016/j.febslet.2011.06.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21729698"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21729698"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Sarah Theresa Boyle, Valentina Poltavets, Jasreen Kular, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41556-020-0523-y"}], "href": "https://doi.org/10.1038/s41556-020-0523-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32451439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32451439"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chuang Li, Ying Maggie Chen "}, {"type": "b", "children": [{"type": "t", "text": "Endoplasmic Reticulum-Associated Biomarkers for Molecular Phenotyping of Rare Kidney Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22042161"}], "href": "https://doi.org/10.3390/ijms22042161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33671535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33671535"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Keiko Nohara, Yukiyo Tateishi, Takehiro Suzuki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Late-onset increases in oxidative stress and other tumorigenic activities and tumors with a Ha-ras mutation in the liver of adult male C3H mice gestationally exposed to arsenic."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Toxicol Sci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/toxsci/kfs203"}], "href": "https://doi.org/10.1093/toxsci/kfs203"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22700541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22700541"}]}]}]}
Proteins	CREL2_HUMAN
NCBI Gene ID	79174
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CRELD2 has 8,205 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 105 datasets.

Click the + buttons to view associations for CRELD2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CRELD2 Gene

Functional Associations

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

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by CRELD2 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CRELD2 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 CRELD2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of CRELD2 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CRELD2 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 CRELD2 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 CRELD2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CRELD2 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 CRELD2 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 CRELD2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of CRELD2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CRELD2 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 CRELD2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with CRELD2 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CRELD2 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 CRELD2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CRELD2 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 CRELD2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of CRELD2 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CRELD2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CRELD2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CRELD2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CRELD2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CRELD2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CRELD2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with CRELD2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of CRELD2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CRELD2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CRELD2 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 CRELD2 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 CRELD2 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 CRELD2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CRELD2 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 CRELD2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CRELD2 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 CRELD2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of CRELD2 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with CRELD2 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing CRELD2 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of CRELD2 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.