EPHB6 Gene

HGNC Family	Sterile alpha motif (SAM) domain containing (SAMD), Receptor kinases, Fibronectin type III domain containing
Name	EPH receptor B6
Description	This gene encodes a member of a family of transmembrane proteins that function as receptors for ephrin-B family proteins. Unlike other members of this family, the encoded protein does not contain a functional kinase domain. Activity of this protein can influence cell adhesion and migration. Expression of this gene is downregulated during tumor progression, suggesting that the protein may suppress tumor invasion and metastasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n EPHB6, a catalytically inactive member of the Eph receptor family, plays multifaceted roles in both the immune system and cancer progression. In the adaptive immune compartment, EPHB6 is highly expressed on T lymphocytes where it functions as a critical costimulatory molecule. Upon T‐cell receptor engagement, EPHB6 rapidly translocates to membrane regions enriched in aggregated TCR complexes, where it facilitates downstream signaling events—including p38 MAPK activation and modulation of proximal molecules such as ZAP‑70—that promote lymphokine secretion and robust T‐cell proliferation."}, {"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 context of cancer, loss or significant downregulation of EPHB6 expression has been linked to malignant progression. In melanocytic and breast carcinomas, for example, EPHB6 is frequently transcriptionally silenced—often via promoter hypermethylation—which correlates with increased invasiveness and metastatic potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Re-expression of EPHB6 in invasive tumor cells has been shown to restore actin‐dependent spreading and adhesion, thereby suppressing cell migration and invasiveness. This antimigratory effect appears to be mediated through its ability to initiate intracellular signaling via adaptor proteins (such as c‑Cbl) and through concentration‐dependent (biphasic) modulation of cell adhesion and movement."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, EPHB6 is capable of forming heteromeric receptor complexes with kinase‐competent Eph receptors—including interactions with EPHA2—that may contribute to its metastasis suppressor function by sequestering or modulating the activity of oncogenic Eph receptors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies define EPHB6 as a pivotal modulator of T cell activation and as a suppressor of tumor cell invasiveness. Its ability to influence cytoskeletal dynamics and intracellular signaling underscores its dual role in maintaining immune responsiveness and in restraining cancer progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hongyu Luo, Guang Yu, Johanne Tremblay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EphB6-null mutation results in compromised T cell function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI21846"}], "href": "https://doi.org/10.1172/JCI21846"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15599401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15599401"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hongyu Luo, Guang Yu, Yulian Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "EphB6 crosslinking results in costimulation of T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI15883"}], "href": "https://doi.org/10.1172/JCI15883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12393850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12393850"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Christian Hafner, Frauke Bataille, Stefanie Meyer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of EphB6 expression in metastatic melanoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14612926"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14612926"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Brian P Fox, Raj P Kandpal "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2005.11.174"}], "href": "https://doi.org/10.1016/j.bbrc.2005.11.174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16364251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16364251"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lokesh Bhushan, Raj P Kandpal "}, {"type": "b", "children": [{"type": "t", "text": "EphB6 receptor modulates micro RNA profile of breast carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0022484"}], "href": "https://doi.org/10.1371/journal.pone.0022484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21811619"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21811619"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Luke Truitt, Tanya Freywald, John DeCoteau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-1710"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-1710"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20086179"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20086179"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hiroshi Matsuoka, Hiroya Obama, Meghan L Kelly, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration."}]}, {"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.M500010200"}], "href": "https://doi.org/10.1074/jbc.M500010200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15955811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15955811"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Brian P Fox, Raj P Kandpal "}, {"type": "b", "children": [{"type": "t", "text": "A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Genomics Proteomics (2011)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21737611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21737611"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Caleb M Bailey, Paul M Kulesa "}, {"type": "b", "children": [{"type": "t", "text": "Dynamic interactions between cancer cells and the embryonic microenvironment regulate cell invasion and reveal EphB6 as a metastasis suppressor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-13-0673"}], "href": "https://doi.org/10.1158/1541-7786.MCR-13-0673"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24836890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24836890"}]}]}]}
Synonyms	HEP
Proteins	EPHB6_HUMAN
NCBI Gene ID	2051
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

EPHB6 has 6,873 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 120 datasets.

Click the + buttons to view associations for EPHB6 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of EPHB6 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 EPHB6 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with EPHB6 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with EPHB6 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 EPHB6 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing EPHB6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing EPHB6 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with EPHB6 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 EPHB6 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 EPHB6 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with EPHB6 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with EPHB6 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by EPHB6 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DGIdb Drug Targets 2026	interacting drugs for EPHB6 protein from the DGIdb Drug Targets 2026 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with EPHB6 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 EPHB6 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 EPHB6 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 EPHB6 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with EPHB6 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 EPHB6 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 EPHB6 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of EPHB6 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 EPHB6 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 EPHB6 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with EPHB6 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 EPHB6 from the GeneSigDB Published Gene Signatures dataset.