HECW2 Gene

HGNC Family	C2 domain containing
Name	HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2
Description	This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HECW2 is a HECT‐type E3 ubiquitin protein ligase with pleiotropic functions that emerge in diverse tissues and disease settings. In endothelial cells, HECW2 has been shown to physically interact with AMOTL1 and enhance its stability via lysine 63‐linked ubiquitination, thereby contributing to the stabilization of cell–cell junctions and helping to regulate angiogenic sprouting ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. \n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the nuclear compartment, particularly in the context of laminopathies, HECW2 is upregulated in cells expressing mutant lamin A. Here, HECW2 mediates ubiquitination of key nuclear proteins – including PCNA, lamin B1, and the heterochromatin binding proteins HP1α and HP1β – promoting their proteasomal degradation and thereby contributing to nuclear protein homeostasis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In neurodevelopment, multiple studies have implicated HECW2 dysfunction in a spectrum of disorders. De novo heterozygous missense variants in HECW2 have been associated with intellectual disability, hypotonia, seizures, and absent language, most likely through dominant‐negative effects that disrupt its ability to stabilize and potentiate p73 activity—a key regulator of neuronal differentiation and cell survival ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "]. Notably, even a recently reported homozygous nonsense variant further underscores the essential role of HECW2 in proper brain development.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In oncogenesis, HECW2 is targeted by miR‐944 in cervical cancer cells, suggesting that its downregulation may contribute to tumor progression by altering critical ubiquitination pathways ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "]. In addition, network analyses in ulcerative colitis have revealed HECW2 among central interactors, pointing to a potential yet to be fully elucidated role in inflammatory conditions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Lastly, genetic studies in a porcine model of male infertility have highlighted HECW2 as a candidate gene involved in acrosome formation and chromatin remodeling during spermatogenesis ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "].\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, HECW2 functions as a multifaceted E3 ubiquitin ligase—regulating cell junction stability in endothelial cells, maintaining nuclear protein turnover in laminopathic cells, and ensuring proper neurodevelopment via stabilization of key transcription factors—as well as playing roles in oncogenesis and spermatogenesis. Dysregulation of HECW2, whether by mutation or altered expression, is linked to neurodevelopmental disorders, certain cancers, and infertility, underscoring its broad biomedical significance.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kyu-Sung Choi, Hyun-Jung Choi, Jin-Kyu Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2016.07.015"}], "href": "https://doi.org/10.1016/j.cellsig.2016.07.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27498087"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27498087"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Vidhya Krishnamoorthy, Richa Khanna, Veena K Parnaik "}, {"type": "b", "children": [{"type": "t", "text": "E3 ubiquitin ligase HECW2 targets PCNA and lamin B1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Cell Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2018.05.008"}], "href": "https://doi.org/10.1016/j.bbamcr.2018.05.008"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29753763"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29753763"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Vidhya Krishnamoorthy, Richa Khanna, Veena K Parnaik "}, {"type": "b", "children": [{"type": "t", "text": "E3 ubiquitin ligase HECW2 mediates the proteasomal degradation of HP1 isoforms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2018.07.003"}], "href": "https://doi.org/10.1016/j.bbrc.2018.07.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30208514"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30208514"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jonatan Halvardson, Jin J Zhao, Ammar Zaghlool, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in HECW2 are associated with intellectual disability and epilepsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmedgenet-2016-103814"}], "href": "https://doi.org/10.1136/jmedgenet-2016-103814"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27334371"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27334371"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Esther R Berko, Megan T Cho, Christine Eng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmedgenet-2016-103943"}], "href": "https://doi.org/10.1136/jmedgenet-2016-103943"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27389779"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27389779"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Tomoe Yanagishita, Takuya Hirade, Keiko Shimojima Yamamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HECW2-related disorder in four Japanese patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.62363"}], "href": "https://doi.org/10.1002/ajmg.a.62363"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34047014"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34047014"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Qian Lu, Meng-Na Zhang, Xiu-Yu Shi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of HECW2 variants with developmental and epileptic encephalopathy and knockdown of zebrafish hecw2a."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.61958"}], "href": "https://doi.org/10.1002/ajmg.a.61958"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33205896"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33205896"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Ev-Christin Heide, Oliver Puk, Saskia Biskup, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel likely pathogenic heterozygous HECW2 missense variant in a family with variable expressivity of neurodevelopmental delay, hypotonia, and epileptiform EEG patterns."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.62427"}], "href": "https://doi.org/10.1002/ajmg.a.62427"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34327820"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34327820"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Al Mehdi Krami, Aymane Bouzidi, Majida Charif, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A homozygous nonsense HECW2 variant is associated with neurodevelopmental delay and intellectual disability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2022.104515"}], "href": "https://doi.org/10.1016/j.ejmg.2022.104515"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35487419"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35487419"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hong Xie, Linkiat Lee, Patrick Scicluna, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel functions and targets of miR-944 in human cervical cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.29160"}], "href": "https://doi.org/10.1002/ijc.29160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25156441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25156441"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Shasha Su, Wenjie Kong, Jing Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrated analysis of DNA methylation and gene expression profiles identified S100A9 as a potential biomarker in ulcerative colitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biosci Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BSR20202384"}], "href": "https://doi.org/10.1042/BSR20202384"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33185247"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33185247"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Anu Sironen, Pekka Uimari, Szabolcs Nagy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knobbed acrosome defect is associated with a region containing the genes STK17b and HECW2 on porcine chromosome 15."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Genomics (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2164-11-699"}], "href": "https://doi.org/10.1186/1471-2164-11-699"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21143916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21143916"}]}]}]}
Synonyms	NEDL2, NDHSAL
Proteins	HECW2_HUMAN
NCBI Gene ID	57520
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

HECW2 has 5,498 functional associations with biological entities spanning 9 categories (molecular profile, organism, disease, phenotype or trait, functional term, phrase or reference, chemical, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 115 datasets.

Click the + buttons to view associations for HECW2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

HECW2 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 HECW2 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 HECW2 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 HECW2 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 HECW2 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 RNA-seq	tissue samples with high or low expression of HECW2 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 HECW2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of HECW2 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 HECW2 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 HECW2 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 HECW2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with HECW2 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 HECW2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of HECW2 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 HECW2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with HECW2 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CM4AI KOLF21J CRISPRi Gene Perturbation Atlas	gene perturbations changing expression of HECW2 gene from the CM4AI KOLF21J CRISPRi Gene Perturbation Atlas dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing HECW2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing HECW2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing HECW2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing HECW2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with HECW2 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 HECW2 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 HECW2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with HECW2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with HECW2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with HECW2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with HECW2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of HECW2 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 HECW2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with HECW2 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 HECW2 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 HECW2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with HECW2 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 HECW2 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 HECW2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of HECW2 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 HECW2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with HECW2 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with HECW2 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 HECW2 from the GeneSigDB Published Gene Signatures dataset.