EHD4 Gene

HGNC Family	EF-hand domain containing
Name	EH-domain containing 4
Description	Enables cadherin binding activity. Involved in endocytic recycling and protein homooligomerization. Located in endoplasmic reticulum and recycling endosome membrane. [provided by Alliance of Genome Resources, Mar 2025]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EHD4 is emerging as a versatile regulator of endocytic trafficking that functions at multiple levels of the endosomal system. Studies using specific peptide antibodies have shown that endogenous EHD4 localizes to Rab5‐, EEA1‐, and Arf6‐positive early endosomes and that loss of EHD4 expression leads to enlarged, Rab5‐enriched early endosomes that accumulate recycling and degradative cargo."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In this context, EHD4 interacts with EHD1—likely through hetero‐dimerization—to coordinate the exit of cargo from early endosomes and facilitate membrane vesiculation from tubular recycling endosomes, a function that is comparable to that of EHD1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in general receptor sorting and recycling, EHD4 participates in specialized cellular processes. In endothelial cells undergoing angiogenesis, for example, the F‐BAR protein PACSIN2 recruits EHD4 together with MICAL‐L1 to form a recycling endosome–like tubular structure at the rear of asymmetric adherens junctions. This PACSIN2/EHD4/MICAL‐L1 complex is crucial for the local trafficking of VE‐cadherin and the coordination of polarized, collective endothelial migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n EHD4 also plays a key role in cellular differentiation and development. Genetic deletion of Ehd4 in mice results in defects in male germ cell development that include altered seminiferous tubule architecture, increased apoptosis, and reduced sperm counts, collectively contributing to compromised fertility. Notably, in the Ehd4–null testis, compensatory up‐regulation of other EHD proteins, such as EHD1, may partially ameliorate the phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, in sensory hair cells EHD4 interacts with cadherin 23 in a calcium‐sensitive manner, suggesting a role in regulating cadherin 23 trafficking and localization that could be important for auditory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the context of viral infection, EHD4 acts as a cofactor exploited by HIV‐1 Nef to enhance virus infectivity; depletion of EHD4 (together with Ezrin) significantly reduces the ability of Nef to potentiate viral infectivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these observations demonstrate that EHD4 is integral to the regulation of receptor transport and endocytic recycling—from controlling early endosome dynamics and vesicular fission to modulating specialized processes such as cell–cell junction remodeling during angiogenesis, germ cell development, and even virus-host interactions. This multifaceted involvement underscores the importance of EHD4, both as an individual regulator and as a cooperative partner with other EHD family members, in maintaining cellular homeostasis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mahak Sharma, Naava Naslavsky, Steve Caplan "}, {"type": "b", "children": [{"type": "t", "text": "A role for EHD4 in the regulation of early endosomal transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0854.2008.00732.x"}], "href": "https://doi.org/10.1111/j.1600-0854.2008.00732.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18331452"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18331452"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tyler Jones, Naava Naslavsky, Steve Caplan "}, {"type": "b", "children": [{"type": "t", "text": "Eps15 Homology Domain Protein 4 (EHD4) is required for Eps15 Homology Domain Protein 1 (EHD1)-mediated endosomal recruitment and fission."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0239657"}], "href": "https://doi.org/10.1371/journal.pone.0239657"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32966336"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32966336"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Bishuang Cai, Sai Srinivas Panapakkam Giridharan, Jing Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential roles of C-terminal Eps15 homology domain proteins as vesiculators and tubulators of recycling endosomes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.488627"}], "href": "https://doi.org/10.1074/jbc.M113.488627"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24019528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24019528"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Tsveta S Malinova, Ana Angulo-Urarte, Julian Nüchel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-021-22873-y"}], "href": "https://doi.org/10.1038/s41467-021-22873-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33972531"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33972531"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Manju George, Mark A Rainey, Mayumi Naramura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ehd4 is required to attain normal prepubertal testis size but dispensable for fertility in male mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genesis (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvg.20620"}], "href": "https://doi.org/10.1002/dvg.20620"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20213691"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20213691"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Soma Sengupta, Manju George, Katharine K Miller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EHD4 and CDH23 are interacting partners in cochlear hair cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.025668"}], "href": "https://doi.org/10.1074/jbc.M109.025668"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19487694"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19487694"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Christelle Brégnard, Alessia Zamborlini, Marjorie Leduc, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative proteomic analysis of HIV-1 particles reveals a role for Ezrin and EHD4 in the Nef-dependent increase of virus infectivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.02477-12"}], "href": "https://doi.org/10.1128/JVI.02477-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23325686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23325686"}]}]}]}
Synonyms	PAST4
Proteins	EHD4_HUMAN
NCBI Gene ID	30844
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

EHD4 has 8,189 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 124 datasets.

Click the + buttons to view associations for EHD4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of EHD4 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 EHD4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with EHD4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with EHD4 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 EHD4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of EHD4 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 EHD4 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 EHD4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing EHD4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing EHD4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with EHD4 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 EHD4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with EHD4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with EHD4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with EHD4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 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 EHD4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with EHD4 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 EHD4 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 EHD4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of EHD4 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 EHD4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with EHD4 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with EHD4 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 EHD4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with EHD4 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.