HYAL2 Gene

Name	hyaluronoglucosaminidase 2
Description	This gene encodes a weak acid-active hyaluronidase. The encoded protein is similar in structure to other more active hyaluronidases. Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix. Hyaluronan and fragments of hyaluronan are thought to be involved in cell proliferation, migration and differentiation. Although it was previously thought to be a lysosomal hyaluronidase that is active at a pH below 4, the encoded protein is likely a GPI-anchored cell surface protein. This hyaluronidase serves as a receptor for the oncogenic virus Jaagsiekte sheep retrovirus. The gene is one of several related genes in a region of chromosome 3p21.3 associated with tumor suppression. This gene encodes two alternatively spliced transcript variants which differ only in the 5' UTR.[provided by RefSeq, Mar 2010]
Summary	{"type": "root", "children": [{"type": "t", "text": "<head>\n <meta charset=\"UTF-8\">\n <title>Summary of HYAL2 Function</title>\n </head>\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n HYAL2 is a glycosylphosphatidylinositol‑anchored cell‐surface enzyme that plays a critical role in the initial step of hyaluronan (HA) catabolism. On one hand, HYAL2 expressed on platelets is sufficient to cleave extracellular HA into specific low‐molecular‐weight fragments that can trigger inflammatory and angiogenic signaling events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In airway epithelial cells, reactive oxygen species induce HYAL2 expression and activity via the p38MAPK pathway, leading to sustained HA fragmentation under conditions of oxidative stress—findings that correlate in vivo with increased HYAL2 immunoreactivity in smokers’ bronchial secretions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In vivo, HYAL2 is essential for normal HA turnover, as demonstrated by studies in HYAL2‐deficient mice which exhibit markedly elevated plasma HA levels, altered HA molecular weight distribution, and defects in craniovertebral bone formation and hematological homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, HYAL2 serves as the receptor for certain retroviral envelope proteins; binding of the jaagsiekte sheep retrovirus envelope to HYAL2 disrupts its association with regulatory partners (such as the RON receptor tyrosine kinase), leading to activation of oncogenic signaling pathways in bronchial epithelial cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of cancer progression, elevated HYAL2 expression has been linked to a more aggressive phenotype. For instance, in breast cancer, high HYAL2 levels are associated with enhanced degradation of high–molecular‑weight HA into low–molecular‑weight fragments, which in turn inhibit tumor‐suppressive Hippo signaling and promote tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In parallel, studies using knockout models further demonstrate that HYAL2 is necessary for clearance of high–molecular‑weight HA from lymph and serum and for proper endocytosis by liver nonparenchymal cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted role of HYAL2 in maintaining extracellular matrix homeostasis, modulating inflammation and angiogenesis, and influencing oncogenic transformation and tumor progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carol de la Motte, Julie Nigro, Amit Vasanji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2353/ajpath.2009.080831"}], "href": "https://doi.org/10.2353/ajpath.2009.080831"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19443707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19443707"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Maria E Monzon, Nevis Fregien, Nathalie Schmid, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation."}]}, {"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.M110.135194"}], "href": "https://doi.org/10.1074/jbc.M110.135194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20554532"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20554532"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Laurence Jadin, Xiaoli Wu, Hao Ding, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Skeletal and hematological anomalies in HYAL2-deficient mice: a second type of mucopolysaccharidosis IX?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.08-111997"}], "href": "https://doi.org/10.1096/fj.08-111997"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18772348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18772348"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Alla Danilkovitch-Miagkova, Fuh-Mei Duh, Igor Kuzmin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0837136100"}], "href": "https://doi.org/10.1073/pnas.0837136100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12676986"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12676986"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takuya Ooki, Naoko Murata-Kamiya, Atsushi Takahashi-Kanemitsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2019.04.018"}], "href": "https://doi.org/10.1016/j.devcel.2019.04.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31080060"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31080060"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Virginie Bourguignon, Bruno Flamion "}, {"type": "b", "children": [{"type": "t", "text": "Respective roles of hyaluronidases 1 and 2 in endogenous hyaluronan turnover."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.201500178R"}], "href": "https://doi.org/10.1096/fj.201500178R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26887442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26887442"}]}]}]}
Synonyms	LUCA2
Proteins	HYAL2_HUMAN
NCBI Gene ID	8692
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HYAL2 has 7,380 functional associations with biological entities spanning 8 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) extracted from 119 datasets.

Click the + buttons to view associations for HYAL2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of HYAL2 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 HYAL2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HYAL2 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 HYAL2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HYAL2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HYAL2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HYAL2 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 HYAL2 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 HYAL2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HYAL2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with HYAL2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of HYAL2 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 HYAL2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DGIdb Drug Targets 2026	interacting drugs for HYAL2 protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with HYAL2 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 HYAL2 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 HYAL2 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 HYAL2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HYAL2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at HYAL2 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 HYAL2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HYAL2 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 HYAL2 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 HYAL2 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with HYAL2 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 HYAL2 from the GeneSigDB Published Gene Signatures dataset.