Atlas of Genetics and Cytogenetics in Oncology and Haematology

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EPHB6 (EPH receptor B6)

Written2012-02Lokesh Bhushan, Raj P Kandpal
Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA

(Note : for Links provided by Atlas : click)


HGNC Alias symbHEP
HGNC Previous nameEphB6
LocusID (NCBI) 2051
Atlas_Id 40471
Location 7q34  [Link to chromosome band 7q34]
Location_base_pair Starts at 142855076 and ends at 142871093 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping EPHB6.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EPHB6 (7q34)::YLPM1 (14q24.3)YLPM1 (14q24.3)::EPHB6 (7q34)


Note EphB6 is located on chromosome 7q33-q35.
  The chromosomal location of EPHB6 is indicated at interval q33-q35. Adapted from GeneCards.
Description Size: 16056 bases.
Orientation: plus strand.
Transcription EphB6 mRNA size is 4044 bp.
Pseudogene Not reported.


Note 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).
  Schematic representation of various domains in EphB6 protein.
Description 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).
Expression 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).
Localisation Cellular. EphB6 is a transmembrane protein.
Function 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.
Homology 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 Non-small cell lung cancer
Note 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).
Entity Breast cancer
Note 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).
Entity Melanoma
Note The progression of melanoma to metastasis has been correlated to progressive decrease of EphB6 expression (Hafner et al., 2003).
Entity Neuroblastoma
Note The levels of EphB6 have been characterized as prognostic indicators in neuroblastoma (Tang et al., 1999b; Tang et al., 2000).
Entity Leukemia and T-cell development
Note 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).
Entity Colorectal and colon cancer
Note 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).


Expression of two novel eph-related receptor protein tyrosine kinases in mammary gland development and carcinogenesis.
Andres AC, Reid HH, Zurcher G, Blaschke RJ, Albrecht D, Ziemiecki A.
Oncogene. 1994 May;9(5):1461-7.
PMID 8152808
Distinct genetic alterations in colorectal cancer.
Ashktorab H, Schaffer AA, Daremipouran M, Smoot DT, Lee E, Brim H.
PLoS One. 2010 Jan 26;5(1):e8879.
PMID 20126641
EphB6 receptor modulates micro RNA profile of breast carcinoma cells.
Bhushan L, Kandpal RP.
PLoS One. 2011;6(7):e22484. Epub 2011 Jul 19.
PMID 21811619
Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome.
Brantley-Sieders DM, Jiang A, Sarma K, Badu-Nkansah A, Walter DL, Shyr Y, Chen J.
PLoS One. 2011;6(9):e24426. Epub 2011 Sep 15.
PMID 21935409
Cloning, characterization, and differential expression of MDK2 and MDK5, two novel receptor tyrosine kinases of the eck/eph family.
Ciossek T, Lerch MM, Ullrich A.
Oncogene. 1995 Nov 16;11(10):2085-95.
PMID 7478528
The ephrins and Eph receptors in neural development.
Flanagan JG, Vanderhaeghen P.
Annu Rev Neurosci. 1998;21:309-45. (REVIEW)
PMID 9530499
A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines.
Fox BP, Kandpal RP.
Cancer Genomics Proteomics. 2011 Jul-Aug;8(4):185-93.
PMID 21737611
Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines.
Fox BP, Tabone CJ, Kandpal RP.
Biochem Biophys Res Commun. 2006 Apr 21;342(4):1263-72. Epub 2006 Feb 28.
PMID 16516143
cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases.
Fox GM, Holst PL, Chute HT, Lindberg RA, Janssen AM, Basu R, Welcher AA.
Oncogene. 1995 Mar 2;10(5):897-905.
PMID 7898931
Eph receptors and neural plasticity.
Gerlai R.
Nat Rev Neurosci. 2001 Mar;2(3):205-9.
PMID 11256081
A new member of the Eph family of receptors that lacks protein tyrosine kinase activity.
Gurniak CB, Berg LJ.
Oncogene. 1996 Aug 15;13(4):777-86.
PMID 8761299
Somatic mutations and germline sequence variants in patients with familial colorectal cancer.
Gylfe AE, Sirkia J, Ahlsten M, Jarvinen H, Mecklin JP, Karhu A, Aaltonen LA.
Int J Cancer. 2010 Dec 15;127(12):2974-80. doi: 10.1002/ijc.25529.
PMID 21351276
Loss of EphB6 expression in metastatic melanoma.
Hafner C, Bataille F, Meyer S, Becker B, Roesch A, Landthaler M, Vogt T.
Int J Oncol. 2003 Dec;23(6):1553-9.
PMID 14612926
Regulation of repulsion versus adhesion by different splice forms of an Eph receptor.
Holmberg J, Clarke DL, Frisen J.
Nature. 2000 Nov 9;408(6809):203-6.
PMID 11089974
Signal transfer by Eph receptors.
Kalo MS, Pasquale EB.
Cell Tissue Res. 1999 Oct;298(1):1-9. (REVIEW)
PMID 10555534
Tyrosine kinase-deficient EphB6 receptor-dependent alterations in proteomic profiles of invasive breast carcinoma cells as determined by difference gel electrophoresis.
Kandpal RP.
Cancer Genomics Proteomics. 2010 Sep-Oct;7(5):253-60.
PMID 20952760
Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo.
Kullander K, Mather NK, Diella F, Dottori M, Boyd AW, Klein R.
Neuron. 2001 Jan;29(1):73-84.
PMID 11182082
The N-terminal globular domain of Eph receptors is sufficient for ligand binding and receptor signaling.
Labrador JP, Brambilla R, Klein R.
EMBO J. 1997 Jul 1;16(13):3889-97.
PMID 9233799
Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization.
Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M, Kravets L, Boyd AW.
J Biol Chem. 1998 Aug 7;273(32):20228-37.
PMID 9685371
Defining brain wiring patterns and mechanisms through gene trapping in mice.
Leighton PA, Mitchell KJ, Goodrich LV, Lu X, Pinson K, Scherz P, Skarnes WC, Tessier-Lavigne M.
Nature. 2001 Mar 8;410(6825):174-9.
PMID 11242070
Embryonic stem cells express multiple Eph-subfamily receptor tyrosine kinases.
Lickliter JD, Smith FM, Olsson JE, Mackwell KL, Boyd AW.
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):145-50.
PMID 8552593
Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells.
Luo H, Wan X, Wu Y, Wu J.
J Immunol. 2001 Aug 1;167(3):1362-70.
PMID 11466354
EphB6 crosslinking results in costimulation of T cells.
Luo H, Yu G, Wu Y, Wu J.
J Clin Invest. 2002 Oct;110(8):1141-50.
PMID 12393850
Expression of a kinase-defective Eph-like receptor in the normal human brain.
Matsuoka H, Iwata N, Ito M, Shimoyama M, Nagata A, Chihara K, Takai S, Matsui T.
Biochem Biophys Res Commun. 1997 Jun 27;235(3):487-92.
PMID 9207182
Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer.
Muller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwable J, Plewka S, Thomas M, Metzger R, Schneider PM, Brandts CH, Berdel WE, Serve H.
Cancer Res. 2005 Mar 1;65(5):1778-82.
PMID 15753374
Expression and function of the Eph A receptors and their ligands ephrins A in the rat thymus.
Munoz JJ, Alonso-C LM, Sacedon R, Crompton T, Vicente A, Jimenez E, Varas A, Zapata AG.
J Immunol. 2002 Jul 1;169(1):177-84.
PMID 12077243
Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6.
Munthe E, Rian E, Holien T, Rasmussen A, Levy FO, Aasheim H.
FEBS Lett. 2000 Jan 21;466(1):169-74.
PMID 10648835
Developmental expression of EphB6 in the thymus: lessons from EphB6 knockout mice.
Shimoyama M, Matsuoka H, Nagata A, Iwata N, Tamekane A, Okamura A, Gomyo H, Ito M, Jishage K, Kamada N, Suzuki H, Tetsuo Noda T, Matsui T.
Biochem Biophys Res Commun. 2002 Oct 18;298(1):87-94.
PMID 12379224
Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma.
Tang XX, Brodeur GM, Campling BG, Ikegaki N.
Clin Cancer Res. 1999a Feb;5(2):455-60.
PMID 10037197
High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.
Tang XX, Evans AE, Zhao H, Cnaan A, London W, Cohn SL, Brodeur GM, Ikegaki N.
Clin Cancer Res. 1999b Jun;5(6):1491-6.
PMID 10389937
Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma.
Tang XX, Zhao H, Robinson ME, Cohen B, Cnaan A, London W, Cohn SL, Cheung NK, Brodeur GM, Evans AE, Ikegaki N.
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10936-41.
PMID 10984508
The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells.
Truitt L, Freywald T, DeCoteau J, Sharfe N, Freywald A.
Cancer Res. 2010 Feb 1;70(3):1141-53. Epub 2010 Jan 19.
PMID 20086179
Eph-related receptors and their ligands: mediators of contact dependent cell interactions.
Xu Q, Wilkinson DG.
J Mol Med (Berl). 1997 Aug;75(8):576-86. (REVIEW)
PMID 9297625
The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer.
Yu J, Bulk E, Ji P, Hascher A, Tang M, Metzger R, Marra A, Serve H, Berdel WE, Wiewroth R, Koschmieder S, Muller-Tidow C.
Clin Cancer Res. 2010 Apr 15;16(8):2275-83. Epub 2010 Apr 6.
PMID 20371680


This paper should be referenced as such :
Bhushan, L ; Kandpal, RP
EPHB6 (EPH receptor B6)
Atlas Genet Cytogenet Oncol Haematol. 2012;16(7):463-466.
Free journal version : [ pdf ]   [ DOI ]

External links


HGNC (Hugo)EPHB6   3396
Entrez_Gene (NCBI)EPHB6    EPH receptor B6
GeneCards (Weizmann)EPHB6
Ensembl hg19 (Hinxton)ENSG00000106123 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000106123 [Gene_View]  ENSG00000106123 [Sequence]  chr7:142855076-142871093 [Contig_View]  EPHB6 [Vega]
ICGC DataPortalENSG00000106123
TCGA cBioPortalEPHB6
Genatlas (Paris)EPHB6
SOURCE (Princeton)EPHB6
Genetics Home Reference (NIH)EPHB6
Genomic and cartography
GoldenPath hg38 (UCSC)EPHB6  -     chr7:142855076-142871093 +  7q34   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)EPHB6  -     7q34   [Description]    (hg19-Feb_2009)
GoldenPathEPHB6 - 7q34 [CytoView hg19]  EPHB6 - 7q34 [CytoView hg38]
Genome Data Viewer NCBIEPHB6 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AL532843 AL832533 BC015495 BC047892 BC051028
RefSeq transcript (Entrez)NM_001280794 NM_001280795 NM_004445
Consensus coding sequences : CCDS (NCBI)EPHB6
Gene ExpressionEPHB6 [ NCBI-GEO ]   EPHB6 [ EBI - ARRAY_EXPRESS ]   EPHB6 [ SEEK ]   EPHB6 [ MEM ]
Gene Expression Viewer (FireBrowse)EPHB6 [ Firebrowse - Broad ]
GenevisibleExpression of EPHB6 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2051
GTEX Portal (Tissue expression)EPHB6
Human Protein AtlasENSG00000106123-EPHB6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO15197   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO15197  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO15197
Domaine pattern : Prosite (Expaxy)EPH_LBD (PS51550)    FN3 (PS50853)    PROTEIN_KINASE_DOM (PS50011)    RECEPTOR_TYR_KIN_V_1 (PS00790)    RECEPTOR_TYR_KIN_V_2 (PS00791)    SAM_DOMAIN (PS50105)   
Domains : Interpro (EBI)Eph_TM    Ephrin_rcpt_lig-bd_dom    FN3_dom    FN3_sf    Galactose-bd-like_sf    Growth_fac_rcpt_cys_sf    Ig-like_fold    Kinase-like_dom_sf    Prot_kinase_dom    SAM    SAM/pointed_sf    Ser-Thr/Tyr_kinase_cat_dom    Tyr-kin_ephrin_A/B_rcpt-like    Tyr_kinase_ephrin_rcpt    Tyr_kinase_rcpt_V_CS   
Domain families : Pfam (Sanger)EphA2_TM (PF14575)    Ephrin_lbd (PF01404)    Ephrin_rec_like (PF07699)    fn3 (PF00041)    PK_Tyr_Ser-Thr (PF07714)    SAM_2 (PF07647)   
Domain families : Pfam (NCBI)pfam14575    pfam01404    pfam07699    pfam00041    pfam07714    pfam07647   
Domain families : Smart (EMBL)EPH_lbd (SM00615)  Ephrin_rec_like (SM01411)  FN3 (SM00060)  SAM (SM00454)  
Conserved Domain (NCBI)EPHB6
AlphaFold pdb e-kbO15197   
Human Protein Atlas [tissue]ENSG00000106123-EPHB6 [tissue]
Protein Interaction databases
IntAct (EBI)O15197
Ontologies - Pathways
Ontology : AmiGOtransmembrane receptor protein tyrosine kinase activity  ephrin receptor activity  transmembrane-ephrin receptor activity  ATP binding  extracellular region  cytosol  plasma membrane  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  multicellular organism development  axon guidance  peptidyl-tyrosine phosphorylation  central nervous system projection neuron axonogenesis  positive regulation of kinase activity  signaling receptor activity  neuron projection  receptor complex  ephrin receptor signaling pathway  
Ontology : EGO-EBItransmembrane receptor protein tyrosine kinase activity  ephrin receptor activity  transmembrane-ephrin receptor activity  ATP binding  extracellular region  cytosol  plasma membrane  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  multicellular organism development  axon guidance  peptidyl-tyrosine phosphorylation  central nervous system projection neuron axonogenesis  positive regulation of kinase activity  signaling receptor activity  neuron projection  receptor complex  ephrin receptor signaling pathway  
Pathways : KEGGAxon guidance   
REACTOMEO15197 [protein]
REACTOME PathwaysR-HSA-3928665 [pathway]   
NDEx NetworkEPHB6
Atlas of Cancer Signalling NetworkEPHB6
Wikipedia pathwaysEPHB6
Orthology - Evolution
GeneTree (enSembl)ENSG00000106123
Phylogenetic Trees/Animal Genes : TreeFamEPHB6
Homologs : HomoloGeneEPHB6
Homology/Alignments : Family Browser (UCSC)EPHB6
Gene fusions - Rearrangements
Fusion : QuiverEPHB6
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerEPHB6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)EPHB6
Exome Variant ServerEPHB6
GNOMAD BrowserENSG00000106123
Varsome BrowserEPHB6
ACMGEPHB6 variants
Genomic Variants (DGV)EPHB6 [DGVbeta]
DECIPHEREPHB6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisEPHB6 
ICGC Data PortalEPHB6 
TCGA Data PortalEPHB6 
Broad Tumor PortalEPHB6
OASIS PortalEPHB6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICEPHB6  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DEPHB6
Mutations and Diseases : HGMDEPHB6
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)EPHB6
DoCM (Curated mutations)EPHB6
CIViC (Clinical Interpretations of Variants in Cancer)EPHB6
NCG (London)EPHB6
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry EPHB6
NextProtO15197 [Medical]
Target ValidationEPHB6
Huge Navigator EPHB6 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDEPHB6
Pharm GKB GenePA27828
Clinical trialEPHB6
DataMed IndexEPHB6
PubMed76 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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