Alternative titles; symbols
HGNC Approved Gene Symbol: EPHB3
Cytogenetic location: 3q27.1 Genomic coordinates (GRCh38): 3:184,561,785-184,582,408 (from NCBI)
See 179610 for background on Eph receptors and their ligands, the ephrins.
Bohme et al. (1993) used PCR to isolate a novel protein tyrosine kinase (PTK), which they termed HEK2 for 'human embryo kinase-2,' from a human embryonic cDNA library. Sequence analysis revealed that HEK2 encodes a 998-amino acid polypeptide having a single putative transmembrane domain, a secretory signal sequence, and 2 fibronectin repeats. Based on sequence homology, Bohme et al. (1993) stated that HEK2 is a member of the EPH/ELK family of tyrosine kinases. Northern blot analysis revealed that HEK2 was expressed as a variable 4.6-kb message in all adult human tissues tested. Southern blot analysis suggested that HEK2 is a single-copy gene in the human genome.
Ruiz et al. (1994) cloned the mouse ortholog of human HEK2. They found that prior to and at the time of heart formation, 7.5 to 8.0 days postcoitum (dpc), Hek2 is expressed in the cranial (rostral) region of the embryo from which a subpopulation of cells gives rise to the rudimentary heart. Between 8.0 and 9.5 dpc, Hek2 mRNA expression is observed in myocardial cells, head mesenchyme, and paraxial mesoderm. Hek2 transcripts are not detected in endocardial cells. After 9.5 dpc, Hek2 expression is downregulated.
Bohme et al. (1996) presented evidence that HEK2 interacts with 2 ligands of EPH-related kinases (LERKs), namely, LERK2 (EFNB1; 300035) and LERK5 (EFNB2; 600527). They reported that coincubation of HEK2- and LERK2-expressing cells induces cell-cell adhesion and aggregation. Additionally, coexpression of HEK2 and LERK2 results in reduced kinase activity of HEK2.
Batlle et al. (2002) showed that beta-catenin (116806) and TCF (see TCF7L2; 602228) inversely control the expression of the EphB2 (600997)/EphB3 receptors and their ligand, ephrin B1, in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes revealed that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3 null mice, the proliferative and differentiated populations intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their downward migratory path, but scattered along crypt and villus. The authors concluded that, in the intestinal epithelium, beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin B system.
Benson et al. (2005) hypothesized that molecules that act as repellents in vertebrate embryonic axonal pathfinding may also inhibit regeneration after injury. By immunohistochemical and Western blot analyses, they showed that Ephb3 was expressed in postnatal myelinating oligodendrocytes of mouse spinal cord. Neurite outgrowth assays with primary central nervous system neurons showed that Ephb3 possessed an inhibitory activity equivalent to the p75 (NGFR; 162010)-mediated activities of Nogo66 (RTN4; 604475), Mag (159460), and Omgp (OMG; 164345) combined. Benson et al. (2005) concluded that EPHB3 is a myelin-based inhibitor of neurite outgrowth.
Using gain- and loss-of-function experiments in mice, Holmberg et al. (2006) found that EphB receptors, in addition to directing cell migration, regulated proliferation in the intestine. EphB2 and EphB3 kinase-dependent signaling promoted cell cycle reentry of intestinal progenitor cells and accounted for about 50% of the mitogenic activity in adult mouse small intestine and colon. Holmberg et al. (2006) concluded EphB receptors are key coordinators of migration and proliferation in the intestinal stem cell niche.
Bohme et al. (1993) used PCR of human-mouse hybrids to map the EPHB3 gene to human chromosome 3q21-qter.
Halford et al. (2000) generated mice deficient in Ryk (600524) and found that they had a distinctive craniofacial appearance, shortened limbs, and postnatal mortality due to feeding and respiratory complications associated with a complete cleft of the secondary palate. Consistent with cleft palate phenocopy in Ephb2/Ephb3-deficient mice and the role of a Drosophila Ryk ortholog, 'Derailed,' in the transduction of repulsive axon pathfinding cues, biochemical data implicated Ryk in signaling mediated by Eph receptors and cell junction-associated Af6 (159559). Halford et al. (2000) concluded that their findings highlighted the importance of signal crosstalk between members of different RTK subfamilies.
Alfaro et al. (2008) observed significantly reduced thymic cellularity in both double-negative (DN; CD4 (186940)-negative/CD8 (see 186910)-negative) and double-positive cells in Ephb2- and/or Ephb3-deficient mice. Adult mutant thymuses had increased proportions of DN cells without significant variation in the percentage of other subsets. Thymocyte number decreased significantly in all compartments from the DN3 (CD44 (107269)-negative/CD25 (147730)-positive) stage onward, without variation in the numbers of either DN1 (CD44-positive/CD25-negative) or DN2 (CD44-positive/CD25-positive) cells. Alfaro et al. (2008) observed the same changes in day-15 fetal Ephb2- and/or Ephb3-deficient thymi and proposed that the adult phenotype results from the gradual accumulation of defects appearing early in ontogeny.
Alfaro, D., Munoz, J. J., Garcia-Ceca, J., Cejalvo, T., Jimenez, E., Zapata, A. Alterations in the thymocyte phenotype of EphB-deficient mice largely affect the double negative cell compartment. Immunology 125: 131-143, 2008. [PubMed: 18397270] [Full Text: https://doi.org/10.1111/j.1365-2567.2008.02828.x]
Batlle, E., Henderson, J. T., Beghtel, H., van den Born, M. M. W., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T., Clevers, H. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 111: 251-263, 2002. [PubMed: 12408869] [Full Text: https://doi.org/10.1016/s0092-8674(02)01015-2]
Benson, M. D., Romero, M. I., Lush, M. E., Lu, Q. R., Henkemeyer, M., Parada, L. F. Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth. Proc. Nat. Acad. Sci. 102: 10694-10699, 2005. [PubMed: 16020529] [Full Text: https://doi.org/10.1073/pnas.0504021102]
Bohme, B., Holtrich, U., Wolf, G., Luzius, H., Grzeschik, K.-H., Strebhardt, K., Rubsamen-Waigmann, H. PCR mediated detection of a new human receptor-tyrosine-kinase, HEK 2. Oncogene 8: 2857-2862, 1993. [PubMed: 8397371]
Bohme, B., VandenBos, T., Cerretti, D. P., Park, L. S., Holtrich, U., Rubsamen-Waigmann, H., Strebhardt, K. Cell-cell adhesion mediated by binding of membrane-anchored ligand LERK-2 to the EPH-related receptor human embryonal kinase 2 promotes tyrosine kinase activity. J. Biol. Chem. 271: 24747-24752, 1996. [PubMed: 8798744] [Full Text: https://doi.org/10.1074/jbc.271.40.24747]
Halford, M. M., Armes, J., Buchert, M., Meskenaite, V., Grail, D., Hibbs, M. L., Wilks, A. F., Farlie, P. G., Newgreen, D. F., Hovens, C. M., Stacker, S. A. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature Genet. 25: 414-418, 2000. [PubMed: 10932185] [Full Text: https://doi.org/10.1038/78099]
Holmberg, J., Genander, M., Halford, M. M., Anneren, C., Sondell, M., Chumley, M. J., Silvany, R. E., Henkemeyer, M., Frisen, J. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125: 1151-1163, 2006. [PubMed: 16777604] [Full Text: https://doi.org/10.1016/j.cell.2006.04.030]
Ruiz, J. C., Conlon, F. L., Robertson, E. J. Identification of novel protein kinases expressed in the myocardium of the developing mouse heart. Mech. Dev. 48: 153-164, 1994. [PubMed: 7893599] [Full Text: https://doi.org/10.1016/0925-4773(94)90056-6]