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Gene Review

Ephb2  -  Eph receptor B2

Mus musculus

Synonyms: Cek5, Drt, ETECK, Ephrin type-B receptor 2, Epth3, ...
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Disease relevance of Ephb2

  • Moreover, while mice singly deficient in either Sek4 or Nuk are viable, most sek4/nuk1 double mutants die immediately after birth primarily due to a cleft palate [1].
  • The axonal localization of Nuk is transient and is not detected after migrations have ceased, suggesting a role for this tyrosine kinase during the early pathfinding and/or fasciculation stages of axonogenesis [2].
  • Tubule-interstitial fibrosis is associated to increases in Ras, Erk, and Akt activation in a renal fibrosis model [3].
  • Erk/MAPK and TGFbeta signaling cause epithelial to mesenchymal transition (EMT) and metastasis in mouse mammary epithelial cells (EpH4) transformed with oncogenic Ras (EpRas) [4].
  • Interestingly, Bcr-Abl(+) CML cell lines established from blast crisis were found to have low Erk MAP kinase activity [5].

High impact information on Ephb2

  • Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region [6].
  • To address the biological functions of the Eph family member Nuk, two mutations in the mouse germline have been generated: a protein null allele (Nuk1) and an allele that encodes a Nuk-beta gal fusion receptor lacking the tyrosine kinase and C-terminal domains (Nuk(lacZ)) [7].
  • Nuk controls pathfinding of commissural axons in the mammalian central nervous system [7].
  • Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation [8].
  • To explore how ephrins could provide positional labels for cell targeting, we tested whether endogenous endothelial and P19 cell EphB1 (ELK) and EphB2 (Nuk) receptors discriminate between different oligomeric forms of an ephrin-B1/Fc fusion ligand [9].

Chemical compound and disease context of Ephb2


Biological context of Ephb2

  • In NG108 neuronal cells, activated EphB2 recruits p120RasGAP, in a fashion that is associated with down-regulation of the Ras-Erk mitogen-activated kinase (MAPK) pathway and neurite retraction [13].
  • Protein localization studies indicate that during early embryogenesis Nuk is confined to the developing nervous system, where it marks segments along the axis of the neural tube in the hindbrain (rhombomeres r2, r3 and r5) and specific morphological bulges of the midbrain and forebrain [2].
  • Inhibition of Erk activation reduces ETS1 phosphorylation and SYN expression [14].
  • These results suggest that vitamin E inhibits cell proliferation and activation of the Erk cascade during promotion of urethane-induced lung tumorigenesis in mice, independent of its antioxidative effect [15].
  • Biochemical analyses correlated Erk activation by Grb2-FAT with its stimulation of cell cycle progression [16].

Anatomical context of Ephb2

  • While mice deficient in Nuk exhibit defects in pathfinding of anterior commissure axons, sek4 mutants have defects in corpus callosum formation [1].
  • Functional assays indicated a correlation between neurite retraction and the ability of the EphB2 mutants to down-regulate Ras-Erk MAPK signaling [13].
  • Most notably, high levels of Nuk protein are found within initial axon outgrowths and associated nerve fibers [2].
  • Sek-3 and Sek-4 have common domains of expression, including r3, r5 and part of the midbrain, as well as specific domains in the diencephalon, telencephalon, spinal cord and in mesodermal and neural crest derivatives [17].
  • Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-alpha production [18].

Associations of Ephb2 with chemical compounds

  • In order to address this question, we examined the inhibitory effect of alpha-tocopheryloxybutyric acid (TSE), an ether derivative of vitamin E that cannot act as an antioxidant in vivo, on cell proliferation and the activation of Erk during promotion of lung tumorigenesis [15].
  • Finally, we showed that FAK regulation of cyclin D1 depends on integrin-mediated cell adhesion and is likely through its activation of the Erk signaling pathway [19].
  • Consistent with this, cholesterol depletion with methyl-beta-cyclodextrin substantially reduces CD38-mediated Akt activation while enhancing CD38-mediated Erk activation [20].
  • We found that binding of RasGAP to the wild-type betaPDGFR was decreased; the activation of Ras and Erk was enhanced, and [3H]thymidine uptake was better in cells cultured on fibronectin than in cells cultured on polylysine [21].
  • Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib [22].

Physical interactions of Ephb2

  • By using a series of deletion and domain substitution mutants, we now report that an N-terminal globular domain of the Nuk/Cek5 receptor is the ligand binding domain of the transmembrane ligand Lerk2 [23].
  • However, the Dok-1 mutant having YF substitutions at the rasGAP-binding sites (Tyr-295 and Tyr-361) also showed incapability of Ras and Erk inhibition [24].

Regulatory relationships of Ephb2

  • Expression of small interfering RNA-escaping silent mutants of p52 or p46 but not p66 ShcA isoform efficiently rescued CSR-induced Erk activation [25].
  • Collectively, this study establishes the physiological significance of the Gab1/Shp2 link in promoting mitogenic signaling through the Erk pathway in mammalian liver regeneration [26].
  • Paradoxically, beta1 integrin stimulation increased EGF-induced Erk activation while increasing expression of the inhibitory p66ShcA isoform [27].
  • Interleukin-7 induces T cell proliferation in the absence of Erk/MAP kinase activity [28].
  • Caveolin-1 blocked the formation of neurites and the phosphorylation of Erk upon bFGF treatment in N2a cells [29].

Other interactions of Ephb2

  • Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells [30].
  • The subcellular localization of Nuk, as well as the presence of fibronectin type III and immunoglobulin-like adhesive domains on the extracellular region, suggest this receptor tyrosine kinase may function to regulate specific cell-cell interactions during early development of the murine nervous system [2].
  • Non-redundant role of Shc in Erk activation by cytoskeletal reorganization [25].
  • KA caused rapid and temporal Erk phosphorylation (at 6h) and Akt dephosphorylation (1-3 days) [31].
  • We also report the sequence and expression pattern in mouse embryos and adult tissues of one of these novel RA-inducible genes, Stra1, and show that it corresponds to the mouse ligand for the Cek5 receptor protein-tyrosine kinase [32].

Analytical, diagnostic and therapeutic context of Ephb2


  1. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. Orioli, D., Henkemeyer, M., Lemke, G., Klein, R., Pawson, T. EMBO J. (1996) [Pubmed]
  2. Immunolocalization of the Nuk receptor tyrosine kinase suggests roles in segmental patterning of the brain and axonogenesis. Henkemeyer, M., Marengere, L.E., McGlade, J., Olivier, J.P., Conlon, R.A., Holmyard, D.P., Letwin, K., Pawson, T. Oncogene (1994) [Pubmed]
  3. Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Martínez-Salgado, C., Fuentes-Calvo, I., García-Cenador, B., Santos, E., López-Novoa, J.M. Exp. Cell Res. (2006) [Pubmed]
  4. ILEI: A cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Waerner, T., Alacakaptan, M., Tamir, I., Oberauer, R., Gal, A., Brabletz, T., Schreiber, M., Jechlinger, M., Beug, H. Cancer Cell (2006) [Pubmed]
  5. Regulation of the Erk2-Elk1 signaling pathway and megakaryocytic differentiation of Bcr-Abl(+) K562 leukemic cells by Gab2. Dorsey, J.F., Cunnick, J.M., Mane, S.M., Wu, J. Blood (2002) [Pubmed]
  6. Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Wybenga-Groot, L.E., Baskin, B., Ong, S.H., Tong, J., Pawson, T., Sicheri, F. Cell (2001) [Pubmed]
  7. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Henkemeyer, M., Orioli, D., Henderson, J.T., Saxton, T.M., Roder, J., Pawson, T., Klein, R. Cell (1996) [Pubmed]
  8. Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Bard-Chapeau, E.A., Hevener, A.L., Long, S., Zhang, E.E., Olefsky, J.M., Feng, G.S. Nat. Med. (2005) [Pubmed]
  9. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Stein, E., Lane, A.A., Cerretti, D.P., Schoecklmann, H.O., Schroff, A.D., Van Etten, R.L., Daniel, T.O. Genes Dev. (1998) [Pubmed]
  10. Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer. Gao, H., Ouyang, X., Banach-Petrosky, W.A., Gerald, W.L., Shen, M.M., Abate-Shen, C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  11. In vivo intracellular signaling as a marker of antiangiogenic activity. Solorzano, C.C., Jung, Y.D., Bucana, C.D., McConkey, D.J., Gallick, G.E., McMahon, G., Ellis, L.M. Cancer Res. (2001) [Pubmed]
  12. Erk 1,2 phosphorylates p27(Kip1): Functional evidence for a role in high glucose-induced hypertrophy of mesangial cells. Wolf, G., Reinking, R., Zahner, G., Stahl, R.A., Shankland, S.J. Diabetologia (2003) [Pubmed]
  13. Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity. Tong, J., Elowe, S., Nash, P., Pawson, T. J. Biol. Chem. (2003) [Pubmed]
  14. The proinflammatory cytokines IL-1beta and TNF-alpha induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway. Gao, B., Calhoun, K., Fang, D. Arthritis Res. Ther. (2006) [Pubmed]
  15. Vitamin E inhibits cell proliferation and the activation of extracellular signal-regulated kinase during the promotion phase of lung tumorigenesis irrespective of antioxidative effect. Yano, T., Yajima, S., Hagiwara, K., Kumadaki, I., Yano, Y., Otani, S., Uchida, M., Ichikawa, T. Carcinogenesis (2000) [Pubmed]
  16. Differential regulation of cell migration and cell cycle progression by FAK complexes with Src, PI3K, Grb7 and Grb2 in focal contacts. Shen, T.L., Guan, J.L. FEBS Lett. (2001) [Pubmed]
  17. Several receptor tyrosine kinase genes of the Eph family are segmentally expressed in the developing hindbrain. Becker, N., Seitanidou, T., Murphy, P., Mattéi, M.G., Topilko, P., Nieto, M.A., Wilkinson, D.G., Charnay, P., Gilardi-Hebenstreit, P. Mech. Dev. (1994) [Pubmed]
  18. Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. Shinohara, H., Inoue, A., Toyama-Sorimachi, N., Nagai, Y., Yasuda, T., Suzuki, H., Horai, R., Iwakura, Y., Yamamoto, T., Karasuyama, H., Miyake, K., Yamanashi, Y. J. Exp. Med. (2005) [Pubmed]
  19. Transcriptional activation of cyclin D1 promoter by FAK contributes to cell cycle progression. Zhao, J., Pestell, R., Guan, J.L. Mol. Biol. Cell (2001) [Pubmed]
  20. CD38 is associated with lipid rafts and upon receptor stimulation leads to Akt/protein kinase B and Erk activation in the absence of the CD3-zeta immune receptor tyrosine-based activation motifs. Zubiaur, M., Fernández, O., Ferrero, E., Salmerón, J., Malissen, B., Malavasi, F., Sancho, J. J. Biol. Chem. (2002) [Pubmed]
  21. Integrins enhance platelet-derived growth factor (PDGF)-dependent responses by altering the signal relay enzymes that are recruited to the PDGF beta receptor. DeMali, K.A., Balciunaite, E., Kazlauskas, A. J. Biol. Chem. (1999) [Pubmed]
  22. Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response. Judde, J.G., Rebucci, M., Vogt, N., de Cremoux, P., Livartowski, A., Chapelier, A., Tran-Perennou, C., Boye, K., Defrance, R., Poupon, M.F., Bras-Gonçalves, R.A. Int. J. Cancer (2007) [Pubmed]
  23. The N-terminal globular domain of Eph receptors is sufficient for ligand binding and receptor signaling. Labrador, J.P., Brambilla, R., Klein, R. EMBO J. (1997) [Pubmed]
  24. Dok-1 tyrosine residues at 336 and 340 are essential for the negative regulation of Ras-Erk signalling, but dispensable for rasGAP-binding. Shinohara, H., Yasuda, T., Yamanashi, Y. Genes Cells (2004) [Pubmed]
  25. Non-redundant role of Shc in Erk activation by cytoskeletal reorganization. Faisal, A., Kleiner, S., Nagamine, Y. J. Biol. Chem. (2004) [Pubmed]
  26. Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Bard-Chapeau, E.A., Yuan, J., Droin, N., Long, S., Zhang, E.E., Nguyen, T.V., Feng, G.S. Mol. Cell. Biol. (2006) [Pubmed]
  27. beta1 integrins modulate p66ShcA expression and EGF-induced MAP kinase activation in fetal lung cells. Smith, S.M., Crowe, D.L., Lee, M.K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  28. Interleukin-7 induces T cell proliferation in the absence of Erk/MAP kinase activity. Crawley, J.B., Willcocks, J., Foxwell, B.M. Eur. J. Immunol. (1996) [Pubmed]
  29. Caveolin-1 inhibits neurite growth by blocking Rac1/Cdc42 and p21-activated kinase 1 interactions. Kang, M.J., Seo, J.S., Park, W.Y. Neuroreport (2006) [Pubmed]
  30. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. Holland, S.J., Gale, N.W., Gish, G.D., Roth, R.A., Songyang, Z., Cantley, L.C., Henkemeyer, M., Yancopoulos, G.D., Pawson, T. EMBO J. (1997) [Pubmed]
  31. Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. Crespo-Biel, N., Canudas, A.M., Camins, A., Pallàs, M. Neurochem. Int. (2007) [Pubmed]
  32. Efficient cloning of cDNAs of retinoic acid-responsive genes in P19 embryonal carcinoma cells and characterization of a novel mouse gene, Stra1 (mouse LERK-2/Eplg2). Bouillet, P., Oulad-Abdelghani, M., Vicaire, S., Garnier, J.M., Schuhbaur, B., Dollé, P., Chambon, P. Dev. Biol. (1995) [Pubmed]
  33. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Holland, S.J., Gale, N.W., Mbamalu, G., Yancopoulos, G.D., Henkemeyer, M., Pawson, T. Nature (1996) [Pubmed]
  34. The coupling of alpha6beta4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation. Mainiero, F., Murgia, C., Wary, K.K., Curatola, A.M., Pepe, A., Blumemberg, M., Westwick, J.K., Der, C.J., Giancotti, F.G. EMBO J. (1997) [Pubmed]
  35. cDNA cloning and characterization of a ligand for the Cek5 receptor protein-tyrosine kinase. Shao, H., Lou, L., Pandey, A., Pasquale, E.B., Dixit, V.M. J. Biol. Chem. (1994) [Pubmed]
  36. Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Holash, J.A., Soans, C., Chong, L.D., Shao, H., Dixit, V.M., Pasquale, E.B. Dev. Biol. (1997) [Pubmed]
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