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Gene Review

EFNA5  -  ephrin-A5

Homo sapiens

Synonyms: AF1, AL-1, EFL5, EPH-related receptor tyrosine kinase ligand 7, EPLG7, ...
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Disease relevance of EFNA5

  • In addition, a soluble form of LERK-7 will induce phosphorylation of eck expressed in a human duodenum adenocarcinoma cell line [1].
  • Unlike other DNA virus proteins, AL1 does not contain the pRb binding consensus, LXCXE, and interacts with plant pRb homo logues (pRBR) through a novel amino acid sequence [2].
  • Earlier studies showed that the viral replication factor, AL1, is sufficient for host induction and interacts with the cell cycle regulator, retinoblastoma (pRb) [2].
  • Plants inoculated with the KEE146 mutant, which retains 16% pRBR binding activity, only developed chlorosis along the veins, and viral DNA, AL1 protein and the host DNA synthesis factor, proliferating cell nuclear antigen, were localized to vascular tissue [2].
  • We performed a phage display screen for human proteins that are exclusively recruited to the phosphorylated form of AF1 and found the stromelysin-1 platelet-derived growth factor-responsive element-binding protein (SPBP) [3].

High impact information on EFNA5

  • Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways [4].
  • Ephrin-A5 induces EphB2-mediated growth cone collapse and neurite retraction in a model system [5].
  • Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation [6].
  • We demonstrate by confocal time-lapse and fluorescence resonance energy transfer microscopy that within minutes of binding ephrin-A5-coated beads, EphA3 receptors assemble into large clusters [7].
  • Here we provide evidence that the domains that signal proteasome-mediated degradation overlap with those that activate transcription, i.e. the activation domains AF-1 and AF-2 [8].

Chemical compound and disease context of EFNA5

  • These results indicated that fully activated AF-1 induces the stimulation of breast cancer growth and that the ratio between AF-1 coactivators and corepressors plays a key role to prevent proliferation of tumor by tamoxifen [9].
  • Additionally, to determine the impact of RXR for erythroid cell development, dominant interfering mutant RXRs, lacking the transcriptional activator functions AF-1 and AF-2, or AF-2 only, or the entire DNA-binding domain, were introduced into erythroid progenitor cells via recombinant retrovirus vectors and analyzed for RXR-specific effects [10].
  • Estrogenic effects of resveratrol in breast cancer cells expressing mutant and wild-type estrogen receptors: role of AF-1 and AF-2 [11].
  • The possible roles of the tyrosine kinase receptor EphA5 and its ligand Ephrin-A5 in axon guidance and axon fasciculation are reviewed [12].
  • AL-1 specifically recognizes N-acetyl-d-glucosamine and is able to bind both E. coli and M. luteus [13].

Biological context of EFNA5


Anatomical context of EFNA5

  • One member, LERK-7, is attached to the cell membrane via glycosyl-phosphatidylinositol linkage and has been found to be a ligand for the eph-family receptors hek, elk, eck, and rek [15].
  • Unexpectedly, we found that many Eph receptors are expressed not only in retinal ganglion cells, but also in tectal cells, In particular, EphA3 mRNA is prominently expressed in the anterior tectum, with a pattern reciprocal to that of ephrin-A2 and ephrin-A5 [18].
  • Similar results were found with membranes from cell lines stably transfected with either ephrin-A5 or ephrin-A2, two previously identified growth cone repellent cell-surface proteins [19].
  • Furthermore, from stages 13-20 ephrin-A2 and ephrin-A5 ligands are only localized to the mesenchyme of the first branchial arch (maxillary and mandibular processes), the target fields for maxillomandibular trigeminal ganglion axons [20].
  • Results indicated an increase in invasive potential of ephrin A5-expressing murine fibroblasts, which was abolished by addition of a Src family kinase inhibitor [16].

Associations of EFNA5 with chemical compounds

  • Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ERalpha, AKT increased the activity of only AF-1 [21].
  • Ephrin-A5 and Ephrin-A2 are ligands for the EphA subfamily of Eph receptor tyrosine kinases, which are expressed in overlapping gradients in the posterior part of the tectum [22].
  • Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein [23].
  • In contrast, hERalpha46 is a powerful inhibitor of hERalpha66 in a cell context where the transactivating function of AF-1 predominates over AF-2 [24].
  • Our results suggest a definitive mechanistic role for E2 in the activity of ER--namely, to alter receptor conformation to promote an association of the amino- and carboxyl-terminal regions, leading to transcriptional synergism between AF-1 and AF-2 [25].

Regulatory relationships of EFNA5


Other interactions of EFNA5

  • Our results indicate that AL1/LERK7 is the preferred high-affinity ligand for HEK, forming a stable 1:1 complex with a dissociation constant of 12 nM [14].
  • While these results suggest that Ephrin-A5 and Ephrin-A2 form part of the posterior repulsive guidance activity, they do not elucidate whether they are necessary components [22].
  • A second mRNA profile that included ephrin-A3, ephrin-A5, and ephrin-B1 was expressed by a subset of tumors [27].
  • Identification and characterization of splice variants of ephrin-A3 and ephrin-A5 [28].
  • A striking correlation of both ephrin A1 and ephrin A5 expression with poor survival (r = -0.470; p = 0.02 and r = -0.562; p < 0.01) was observed [29].

Analytical, diagnostic and therapeutic context of EFNA5

  • Our findings demonstrate the application of biosensor technology in ligand purification and show that AL-1, as has been found for other ligands of the EPH-like RTK family, binds more than one receptor [30].
  • The in vitro AL1 binding specificities of the B components were exchanged by site-directed mutagenesis, but the resulting mutants were not replicated by either A component [31].
  • Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors [32].
  • BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters [32].
  • To test the function of EphA4/ephrin-A5 interactions in muscle precursor migration, we used targeted in ovo electroporation to express ephrin-A5 ectopically specifically in the presumptive limb mesoderm [33].


  1. LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain. Kozlosky, C.J., VandenBos, T., Park, L., Cerretti, D.P., Carpenter, M.K. Cytokine (1997) [Pubmed]
  2. A geminivirus replication protein interacts with the retinoblastoma protein through a novel domain to determine symptoms and tissue specificity of infection in plants. Kong, L.J., Orozco, B.M., Roe, J.L., Nagar, S., Ou, S., Feiler, H.S., Durfee, T., Miller, A.B., Gruissem, W., Robertson, D., Hanley-Bowdoin, L. EMBO J. (2000) [Pubmed]
  3. SPBP is a phosphoserine-specific repressor of estrogen receptor alpha. Gburcik, V., Bot, N., Maggiolini, M., Picard, D. Mol. Cell. Biol. (2005) [Pubmed]
  4. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., Chambon, P. Science (1995) [Pubmed]
  5. Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Himanen, J.P., Chumley, M.J., Lackmann, M., Li, C., Barton, W.A., Jeffrey, P.D., Vearing, C., Geleick, D., Feldheim, D.A., Boyd, A.W., Henkemeyer, M., Nikolov, D.B. Nat. Neurosci. (2004) [Pubmed]
  6. Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation. Winslow, J.W., Moran, P., Valverde, J., Shih, A., Yuan, J.Q., Wong, S.C., Tsai, S.P., Goddard, A., Henzel, W.J., Hefti, F. Neuron (1995) [Pubmed]
  7. Recruitment of Eph receptors into signaling clusters does not require ephrin contact. Wimmer-Kleikamp, S.H., Janes, P.W., Squire, A., Bastiaens, P.I., Lackmann, M. J. Cell Biol. (2004) [Pubmed]
  8. Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RAR gamma degradation and transactivation. Giannì, M., Bauer, A., Garattini, E., Chambon, P., Rochette-Egly, C. EMBO J. (2002) [Pubmed]
  9. Full activation of estrogen receptor alpha activation function-1 induces proliferation of breast cancer cells. Fujita, T., Kobayashi, Y., Wada, O., Tateishi, Y., Kitada, L., Yamamoto, Y., Takashima, H., Murayama, A., Yano, T., Baba, T., Kato, S., Kawabe, Y., Yanagisawa, J. J. Biol. Chem. (2003) [Pubmed]
  10. Retinoid X receptor and c-cerbA/thyroid hormone receptor regulate erythroid cell growth and differentiation. Bartůnĕk, P., Zenke, M. Mol. Endocrinol. (1998) [Pubmed]
  11. Estrogenic effects of resveratrol in breast cancer cells expressing mutant and wild-type estrogen receptors: role of AF-1 and AF-2. Gehm, B.D., Levenson, A.S., Liu, H., Lee, E.J., Amundsen, B.M., Cushman, M., Jordan, V.C., Jameson, J.L. J. Steroid Biochem. Mol. Biol. (2004) [Pubmed]
  12. A link between axon guidance and axon fasciculation suggested by studies of the tyrosine kinase receptor EphA5/REK7 and its ligand ephrin-A5/AL-1. Caras, I.W. Cell Tissue Res. (1997) [Pubmed]
  13. A novel lectin with a fibrinogen-like domain and its potential involvement in the innate immune response of Armigeres subalbatus against bacteria. Wang, X., Rocheleau, T.A., Fuchs, J.F., Hillyer, J.F., Chen, C.C., Christensen, B.M. Insect Mol. Biol. (2004) [Pubmed]
  14. Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor. Lackmann, M., Mann, R.J., Kravets, L., Smith, F.M., Bucci, T.A., Maxwell, K.F., Howlett, G.J., Olsson, J.E., Vanden Bos, T., Cerretti, D.P., Boyd, A.W. J. Biol. Chem. (1997) [Pubmed]
  15. The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome 17. Cerretti, D.P., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Kuefer, M.U., Valentine, V., Shapiro, D.N., Cui, X., Morris, S.W. Genomics (1996) [Pubmed]
  16. Ephrin A5 expression promotes invasion and transformation of murine fibroblasts. Campbell, T.N., Attwell, S., Arcellana-Panlilio, M., Robbins, S.M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  17. Partial nucleotide sequences and expression patterns of frog (Rana pipiens) ephrin-A2 and ephrin-A5 mRNA. Yagita, Y., Barjis, I., Hecht, M., Bach, H., Feldheim, D.A., Scalia, F. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  18. Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. Connor, R.J., Menzel, P., Pasquale, E.B. Dev. Biol. (1998) [Pubmed]
  19. Response of retinal ganglion cell axons to striped linear gradients of repellent guidance molecules. Rosentreter, S.M., Davenport, R.W., Löschinger, J., Huf, J., Jung, J., Bonhoeffer, F. J. Neurobiol. (1998) [Pubmed]
  20. High EphA3 expressing ophthalmic trigeminal sensory axons are sensitive to ephrin-A5-Fc: implications for lobe specific axon guidance. Jayasena, C.S., Flood, W.D., Koblar, S.A. Neuroscience (2005) [Pubmed]
  21. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. Campbell, R.A., Bhat-Nakshatri, P., Patel, N.M., Constantinidou, D., Ali, S., Nakshatri, H. J. Biol. Chem. (2001) [Pubmed]
  22. Eph receptor-ligand interactions are necessary for guidance of retinal ganglion cell axons in vitro. Ciossek, T., Monschau, B., Kremoser, C., Löschinger, J., Lang, S., Müller, B.K., Bonhoeffer, F., Drescher, U. Eur. J. Neurosci. (1998) [Pubmed]
  23. Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Hammer, G.D., Krylova, I., Zhang, Y., Darimont, B.D., Simpson, K., Weigel, N.L., Ingraham, H.A. Mol. Cell (1999) [Pubmed]
  24. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. Flouriot, G., Brand, H., Denger, S., Metivier, R., Kos, M., Reid, G., Sonntag-Buck, V., Gannon, F. EMBO J. (2000) [Pubmed]
  25. Ligand-dependent, transcriptionally productive association of the amino- and carboxyl-terminal regions of a steroid hormone nuclear receptor. Kraus, W.L., McInerney, E.M., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. Cdk5/p35 and Rho-kinase mediate ephrin-A5-induced signaling in retinal ganglion cells. Cheng, Q., Sasaki, Y., Shoji, M., Sugiyama, Y., Tanaka, H., Nakayama, T., Mizuki, N., Nakamura, F., Takei, K., Goshima, Y. Mol. Cell. Neurosci. (2003) [Pubmed]
  27. Human osteosarcoma expresses specific ephrin profiles: implications for tumorigenicity and prognosis. Varelias, A., Koblar, S.A., Cowled, P.A., Carter, C.D., Clayer, M. Cancer (2002) [Pubmed]
  28. Identification and characterization of splice variants of ephrin-A3 and ephrin-A5. Lai, K.O., Ip, F.C., Ip, N.Y. FEBS Lett. (1999) [Pubmed]
  29. Over-expression of Eph and ephrin genes in advanced ovarian cancer: ephrin gene expression correlates with shortened survival. Herath, N.I., Spanevello, M.D., Sabesan, S., Newton, T., Cummings, M., Duffy, S., Lincoln, D., Boyle, G., Parsons, P.G., Boyd, A.W. BMC Cancer (2006) [Pubmed]
  30. Purification of a ligand for the EPH-like receptor HEK using a biosensor-based affinity detection approach. Lackmann, M., Bucci, T., Mann, R.J., Kravets, L.A., Viney, E., Smith, F., Moritz, R.L., Carter, W., Simpson, R.J., Nicola, N.A., Mackwell, K., Nice, E.C., Wilks, A.F., Boyd, A.W. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  31. Geminivirus replication origins have a modular organization. Fontes, E.P., Gladfelter, H.J., Schaffer, R.L., Petty, I.T., Hanley-Bowdoin, L. Plant Cell (1994) [Pubmed]
  32. Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents. Vearing, C., Lee, F.T., Wimmer-Kleikamp, S., Spirkoska, V., To, C., Stylianou, C., Spanevello, M., Brechbiel, M., Boyd, A.W., Scott, A.M., Lackmann, M. Cancer Res. (2005) [Pubmed]
  33. EphA4/ephrin-A5 interactions in muscle precursor cell migration in the avian forelimb. Swartz, M.E., Eberhart, J., Pasquale, E.B., Krull, C.E. Development (2001) [Pubmed]
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