EPHB6 (EPH receptor B6)

2012-02-01   Lokesh Bhushan , Raj P Kandpal 

Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA





EphB6 is located on chromosome 7q33-q35.
Atlas Image
The chromosomal location of EPHB6 is indicated at interval q33-q35. Adapted from GeneCards.


Size: 16056 bases.
Orientation: plus strand.


EphB6 mRNA size is 4044 bp.


Not reported.



The crystal structure of EphB6 has not yet been determined. However, based on amino acid sequence and domain arrangement it is classified as a type I transmembrane protein. It has a highly conserved N-terminal domain in the extracellular region that is involved in ligand recognition and binding (Labrador et al., 1997). The N-terminal domain is followed by a cysteine rich region and two fibronectin type-III repeats. These repeats are involved in mediating protein-protein interactions and receptor dimerization (Lackmann et al., 1998). The intracellular region contains a juxtamembrane domain, a conserved kinase domain, a sterile α-motif (SAM) domain and a PSD95/Dlg/ZO1 (PDZ) domain (Kalo and Pasquale, 1999).
Atlas Image
Schematic representation of various domains in EphB6 protein.


Eph (erythropoietin producing hepatocellular carcinoma) receptors belong to a family of receptor tyrosine kinases, which are activated by binding to ephrin ligands. These receptors are involved in a diverse array of signal transduction processes in humans. Such diversity of signaling and the resulting functional output is partly attributed to differential expression and interactions among these receptors. Based on sequence homology and affinity for ephrin ligands, Eph receptors are classified into A and B groups. EphB6 is a kinase-deficient receptor (Gurniak and Berg, 1996) that has been shown to interact with two kinase-active receptors, namely, EphB2 and EphA2 (Fox and Kandpal, 2011). Ephrin B2 has been reported as a ligand for this receptor (Munthe et al., 2000). The loss of EphB6 expression in breast carcinoma cell lines has been correlated to their invasiveness (Fox and Kandpal, 2004; Fox and Kandpal, 2006), and its role as a tumor suppressor has also been reported (Fox and Kandpal, 2009; Yu et al., 2010).


Eph receptors are expressed in a wide variety of tissues and cells (Andres et al., 1994; Fox et al., 1995; Ciossek et al., 1995; Lickliter et al., 1996; Muñoz et al., 2002). In addition to other tissues and cells, EphB6 receptor expression has been shown in breast, prostate, thymus, mature T-cells and leukemia cells (Shimoyama et al., 2000; Luo et al., 2001; Luo et al., 2002; Fox and Kandpal, 2004; Fox et al., 2006). EphB6 deficient mice develop normally and do not display any abnormality in their general appearance (Shimoyama et al., 2002).


Cellular. EphB6 is a transmembrane protein.


A variety of Eph receptors and their ligands are involved in regulating cell pattern formation during organogenesis (Xu and Wilkinson, 1997; Flanagan and Vanderhaeghen, 1998; Holmberg et al., 2000; Leighton et al., 2001; Kullander et al., 2001; Gerlai, 2001). EphB6 has been shown to facilitate T-cell activation (Luo et al., 2002). Metastasis/invasion suppressor role of EphB6 in non-small cell lung carcinoma and breast carcinoma (Müller-Tidow et al., 2005; Fox and Kandpal, 2009) suggests its involvement in cell adhesion and migration.


Amino acid homology between EphB6 and other EphB family members varies between 47% and 60%. Mouse and human homologs of EphB6 share greater than 90% amino acid identity (Gurniak and Berg, 1996; Matsuoka et al., 1997). The kinase domain in EphB6 is mutated.

Implicated in

Entity name
Non-small cell lung cancer
Altered levels and loss of EphB6 expression have been found in non-small cell lung carcinoma (Tang et al., 1999a; Müller-Tidow et al., 2005; Yu et al., 2010).
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Breast cancer
EphB6 silencing has been observed in breast carcinoma cell lines and some tumors (Fox and Kandpal, 2004; Fox and Kandpal, 2006; Fox and Kandpal, 2009; Truitt et al., 2010). Molecular profiling of breast carcinoma cells with or without EphB6 expression has revealed significant changes in proteins as well as miRNAs (Kandpal, 2010; Bhushan and Kandpal, 2011). However, elevated levels of EphB6 have also been reported in breast tumor specimens (Brantley-Sieders et al., 2011).
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The progression of melanoma to metastasis has been correlated to progressive decrease of EphB6 expression (Hafner et al., 2003).
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The levels of EphB6 have been characterized as prognostic indicators in neuroblastoma (Tang et al., 1999b; Tang et al., 2000).
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Leukemia and T-cell development
EphB6 expression has been implicated in T-cell development, and altered levels of this protein have been observed in leukemia and lymphoma cells (Shimoyama et al., 2000).
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Colorectal and colon cancer
In familial colorectal cancer EphB6 gene shows two missense mutations in germline. These two mutations include change of alanine to proline at position 321 (A321P) and glycine to valine (G914V) at position 914 (Gylfe et al., 2010). Deletions of EphB6 gene locus have also been reported in colon cancer (Ashktorab et al., 2010).


Pubmed IDLast YearTitleAuthors
81528081994Expression of two novel eph-related receptor protein tyrosine kinases in mammary gland development and carcinogenesis.Andres AC et al
201266412010Distinct genetic alterations in colorectal cancer.Ashktorab H et al
218116192011EphB6 receptor modulates micro RNA profile of breast carcinoma cells.Bhushan L et al
219354092011Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome.Brantley-Sieders DM et al
74785281995Cloning, characterization, and differential expression of MDK2 and MDK5, two novel receptor tyrosine kinases of the eck/eph family.Ciossek T et al
95304991998The ephrins and Eph receptors in neural development.Flanagan JG et al
217376112011A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines.Fox BP et al
165161432006Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines.Fox BP et al
78989311995cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases.Fox GM et al
112560812001Eph receptors and neural plasticity.Gerlai R et al
87612991996A new member of the Eph family of receptors that lacks protein tyrosine kinase activity.Gurniak CB et al
213512762010Somatic mutations and germline sequence variants in patients with familial colorectal cancer.Gylfe AE et al
146129262003Loss of EphB6 expression in metastatic melanoma.Hafner C et al
110899742000Regulation of repulsion versus adhesion by different splice forms of an Eph receptor.Holmberg J et al
105555341999Signal transfer by Eph receptors.Kalo MS et al
209527602010Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis.Kandpal RP et al
111820822001Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo.Kullander K et al
92337991997The N-terminal globular domain of Eph receptors is sufficient for ligand binding and receptor signaling.Labrador JP et al
96853711998Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization.Lackmann M et al
112420702001Defining brain wiring patterns and mechanisms through gene trapping in mice.Leighton PA et al
85525931996Embryonic stem cells express multiple Eph-subfamily receptor tyrosine kinases.Lickliter JD et al
114663542001Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells.Luo H et al
123938502002EphB6 crosslinking results in costimulation of T cells.Luo H et al
92071821997Expression of a kinase-defective Eph-like receptor in the normal human brain.Matsuoka H et al
157533742005Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer.Müller-Tidow C et al
120772432002Expression and function of the Eph A receptors and their ligands ephrins A in the rat thymus.Muñoz JJ et al
106488352000Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6.Munthe E et al
123792242002Developmental expression of EphB6 in the thymus: lessons from EphB6 knockout mice.Shimoyama M et al
100371971999Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma.Tang XX et al
103899371999High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.Tang XX et al
109845082000Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma.Tang XX et al
200861792010The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells.Truitt L et al
92976251997Eph-related receptors and their ligands: mediators of contact dependent cell interactions.Xu Q et al
203716802010The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer.Yu J et al

Other Information

Locus ID:

NCBI: 2051
MIM: 602757
HGNC: 3396
Ensembl: ENSG00000106123


dbSNP: 2051
ClinVar: 2051
TCGA: ENSG00000106123


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Axon guidanceKEGGko04360
Axon guidanceKEGGhsa04360
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHB-mediated forward signalingREACTOMER-HSA-3928662
Ephrin signalingREACTOMER-HSA-3928664
EPH-ephrin mediated repulsion of cellsREACTOMER-HSA-3928665


Pubmed IDYearTitleCitations
219354092011Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome.49
200861792010The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells.27
159558112005Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration.24
192344852009EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells.23
123938502002EphB6 crosslinking results in costimulation of T cells.21
146129262003Loss of EphB6 expression in metastatic melanoma.20
163642512006Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR.16
114663542001Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells.15
217376112011A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines.15
218116192011EphB6 receptor modulates micro RNA profile of breast carcinoma cells.14


Lokesh Bhushan ; Raj P Kandpal

EPHB6 (EPH receptor B6)

Atlas Genet Cytogenet Oncol Haematol. 2012-02-01

Online version: http://atlasgeneticsoncology.org/gene/40471/ephb6-(eph-receptor-b6)