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EPHB6 (EPH receptor B6)

Identity

Other namesHEP
MGC129910
MGC129911
HGNC (Hugo) EPHB6
LocusID (NCBI) 2051
Location 7q34
Location_base_pair Starts at 142552776 and ends at 142568847 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

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.

Protein

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).
  

External links

Nomenclature
HGNC (Hugo)EPHB6   3396
Cards
AtlasEPHB6ID40471ch7q34
Entrez_Gene (NCBI)EPHB6  2051  EPH receptor B6
GeneCards (Weizmann)EPHB6
Ensembl (Hinxton)ENSG00000106123 [Gene_View]  chr7:142552776-142568847 [Contig_View]  EPHB6 [Vega]
AceView (NCBI)EPHB6
Genatlas (Paris)EPHB6
WikiGenes2051
SOURCE (Princeton)NM_001280794 NM_001280795 NM_004445
Genomic and cartography
GoldenPath (UCSC)EPHB6  -  7q34   chr7:142552776-142568847 +  7q33-q35   [Description]    (hg19-Feb_2009)
EnsemblEPHB6 - 7q33-q35 [CytoView]
Mapping of homologs : NCBIEPHB6 [Mapview]
OMIM602757   
Gene and transcription
Genbank (Entrez)AL832533 BC015495 BC047892 BC051028 BC056159
RefSeq transcript (Entrez)NM_001280794 NM_001280795 NM_004445
RefSeq genomic (Entrez)AC_000068 AC_000139 NC_000007 NC_018918 NT_007914 NT_079596 NW_001839073 NW_003571040 NW_004929333
Consensus coding sequences : CCDS (NCBI)EPHB6
Cluster EST : UnigeneHs.380089 [ NCBI ]
CGAP (NCI)Hs.380089
Alternative Splicing : Fast-db (Paris)GSHG0027807
Alternative Splicing GalleryENSG00000106123
Gene ExpressionEPHB6 [ NCBI-GEO ]     EPHB6 [ SEEK ]   EPHB6 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO15197 (Uniprot)
NextProtO15197  [Medical]
With graphics : InterProO15197
Splice isoforms : SwissVarO15197 (Swissvar)
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    Fibronectin_type3    Galactose-bd-like    Growth_fac_rcpt_N_dom    Ig-like_fold    Kinase-like_dom    Prot_kinase_dom    SAM    SAM/pointed    SAM_2    Ser-Thr/Tyr_kinase_cat_dom    Tyr-kin_ephrin_A/B_rcpt-like    Tyr_kinase_ephrin_rcpt    Tyr_kinase_rcpt_V_CS   
Related proteins : CluSTrO15197
Domain families : Pfam (Sanger)EphA2_TM (PF14575)    Ephrin_lbd (PF01404)    fn3 (PF00041)    GCC2_GCC3 (PF07699)    Pkinase_Tyr (PF07714)    SAM_2 (PF07647)   
Domain families : Pfam (NCBI)pfam14575    pfam01404    pfam00041    pfam07699    pfam07714    pfam07647   
Domain families : Smart (EMBL)EPH_lbd (SM00615)  FN3 (SM00060)  SAM (SM00454)  
DMDM Disease mutations2051
Blocks (Seattle)O15197
Human Protein AtlasENSG00000106123
Peptide AtlasO15197
HPRD04133
IPIIPI00915412   IPI00005222   IPI00873336   IPI00477059   IPI01015948   IPI00879200   IPI00927375   IPI00927179   IPI00878566   
Protein Interaction databases
DIP (DOE-UCLA)O15197
IntAct (EBI)O15197
FunCoupENSG00000106123
BioGRIDEPHB6
InParanoidO15197
Interologous Interaction database O15197
IntegromeDBEPHB6
STRING (EMBL)EPHB6
Ontologies - Pathways
Ontology : AmiGOreceptor activity  ephrin receptor activity  ATP binding  extracellular region  integral to plasma membrane  parathyroid hormone secretion  calcium ion homeostasis  
Ontology : EGO-EBIreceptor activity  ephrin receptor activity  ATP binding  extracellular region  integral to plasma membrane  parathyroid hormone secretion  calcium ion homeostasis  
Pathways : KEGGAxon guidance   
REACTOMEEPHB6
Protein Interaction DatabaseEPHB6
Wikipedia pathwaysEPHB6
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)EPHB6
SNP (GeneSNP Utah)EPHB6
SNP : HGBaseEPHB6
Genetic variants : HAPMAPEPHB6
1000_GenomesEPHB6 
ICGC programENSG00000106123 
Somatic Mutations in Cancer : COSMICEPHB6 
CONAN: Copy Number AnalysisEPHB6 
Mutations and Diseases : HGMDEPHB6
OMIM602757   
GENETestsEPHB6
Disease Genetic AssociationEPHB6
Huge Navigator EPHB6 [HugePedia]  EPHB6 [HugeCancerGEM]
Genomic VariantsEPHB6  EPHB6 [DGVbeta]
Exome VariantEPHB6
dbVarEPHB6
ClinVarEPHB6
snp3D : Map Gene to Disease2051
General knowledge
Homologs : HomoloGeneEPHB6
Homology/Alignments : Family Browser (UCSC)EPHB6
Phylogenetic Trees/Animal Genes : TreeFamEPHB6
Chemical/Protein Interactions : CTD2051
Chemical/Pharm GKB GenePA27828
Clinical trialEPHB6
Cancer Resource (Charite)ENSG00000106123
Other databases
Probes
Litterature
PubMed45 Pubmed reference(s) in Entrez
CoreMineEPHB6
iHOPEPHB6

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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 ephrins and Eph receptors in neural development.
Flanagan JG, Vanderhaeghen P.
Annu Rev Neurosci. 1998;21:309-45. (REVIEW)
PMID 9530499
 
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
 
Signal transfer by Eph receptors.
Kalo MS, Pasquale EB.
Cell Tissue Res. 1999 Oct;298(1):1-9. (REVIEW)
PMID 10555534
 
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
 
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
 
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
 
T-cell-specific expression of kinase-defective Eph-family receptor protein, EphB6 in normal as well as transformed hematopoietic cells.
Shimoyama M, Matsuoka H, Tamekane A, Ito M, Iwata N, Inoue R, Chihara K, Furuya A, Hanai N, Matsui T.
Growth Factors. 2000;18(1):63-78.
PMID 10831073
 
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
 
Eph receptors and neural plasticity.
Gerlai R.
Nat Rev Neurosci. 2001 Mar;2(3):205-9.
PMID 11256081
 
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
 
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
 
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 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
 
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
 
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
 
Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application.
Fox BP, Kandpal RP.
Biochem Biophys Res Commun. 2004 Jun 11;318(4):882-92.
PMID 15147954
 
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
 
Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR.
Fox BP, Kandpal RP.
Biochem Biophys Res Commun. 2006 Feb 3;340(1):268-76. Epub 2005 Dec 9.
PMID 16364251
 
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
 
EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells.
Fox BP, Kandpal RP.
Oncogene. 2009 Apr 9;28(14):1706-13. Epub 2009 Feb 23.
PMID 19234485
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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Contributor(s)

Written02-2012Lokesh Bhushan, Raj P Kandpal
Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA

Citation

This paper should be referenced as such :
Bhushan L, Kandpal RP . EPHB6 (EPH receptor B6). Atlas Genet Cytogenet Oncol Haematol. February 2012 .
URL : http://AtlasGeneticsOncology.org/Genes/EPHB6ID40471ch7q34.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/handle/2042/47415/02-2012-EPHB6ID40471ch7q34.pdf   [ Bibliographic record ]

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