epha4 receptor


Summary: An eph family receptor found in variety of tissues including BRAIN. During embryogenesis, EphA4 receptor exhibits a diverse spatial and temporal patterns of expression suggesting its role in multiple developmental processes.

Top Publications

  1. Xu Q, Alldus G, Holder N, Wilkinson D. Expression of truncated Sek-1 receptor tyrosine kinase disrupts the segmental restriction of gene expression in the Xenopus and zebrafish hindbrain. Development. 1995;121:4005-16 pubmed
    ..These data suggest that Sek-1, perhaps with other Eph-related receptors, is required for interactions that regulate the segmental identity or movement of cells. ..
  2. Cooke J, Kemp H, Moens C. EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Curr Biol. 2005;15:536-42 pubmed
  3. Weisinger K, Wilkinson D, Sela Donenfeld D. Inhibition of BMPs by follistatin is required for FGF3 expression and segmental patterning of the hindbrain. Dev Biol. 2008;324:213-25 pubmed publisher
  4. Prevost N, Woulfe D, Jiang H, Stalker T, Marchese P, Ruggeri Z, et al. Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets. Proc Natl Acad Sci U S A. 2005;102:9820-5 pubmed
  5. Kramer E, Knott L, Su F, Dessaud E, Krull C, Helmbacher F, et al. Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor-axon pathway selection in the limb. Neuron. 2006;50:35-47 pubmed
    ..work indicated that the pathway into the dorsal limb by lateral motor column (LMC[l]) axons requires the EphA4 receptor, which mediates repulsion elicited by ephrinAs expressed in ventral limb mesoderm...
  6. Deininger K, Eder M, Kramer E, Zieglgänsberger W, Dodt H, Dornmair K, et al. The Rab5 guanylate exchange factor Rin1 regulates endocytosis of the EphA4 receptor in mature excitatory neurons. Proc Natl Acad Sci U S A. 2008;105:12539-44 pubmed publisher
    ..We find that the EphA4 receptor is required for synaptic plasticity in the amygdala, raising the possibility that an underlying mechanism of ..
  7. Bourgin C, Murai K, Richter M, Pasquale E. The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol. 2007;178:1295-307 pubmed
    ..We previously reported that the EphA4 receptor tyrosine kinase regulates spine morphology in hippocampal pyramidal neurons, but the signaling pathways ..
  8. Lai K, Ip F, Cheung J, Fu A, Ip N. Expression of Eph receptors in skeletal muscle and their localization at the neuromuscular junction. Mol Cell Neurosci. 2001;17:1034-47 pubmed
    ..Since actin cytoskeleton is critical to the formation and stability of NMJ, the present findings raise the intriguing possibility that Eph receptors may have a novel role in NMJ formation and/or maintenance. ..
  9. Cruz Orengo L, Figueroa J, Torrado A, Puig A, Whittemore S, Miranda J. Reduction of EphA4 receptor expression after spinal cord injury does not induce axonal regeneration or return of tcMMEP response. Neurosci Lett. 2007;418:49-54 pubmed
    ..non-permissive environment for axonal regeneration after SCI, we questioned whether enhanced-expression of the EphA4 receptor with repulsive activity for axonal outgrowth is potentially responsible for the regenerative failure...

More Information


  1. Lai K, Chen Y, Po H, Lok K, Gong K, Ip N. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. J Biol Chem. 2004;279:13383-92 pubmed
    ..In addition, the present study provides the first demonstration of a potential function of Eph receptors and Jak/Stat proteins at the NMJ. ..
  2. Murai K, Nguyen L, Koolpe M, McLennan R, Krull C, Pasquale E. Targeting the EphA4 receptor in the nervous system with biologically active peptides. Mol Cell Neurosci. 2003;24:1000-11 pubmed
    ..This panel of peptides may lead to the development of pharmaceuticals that differentially target Eph receptors to modulate neuronal function in specific regions of the nervous system. ..
  3. Iiizumi M, Hosokawa M, Takehara A, Chung S, Nakamura T, Katagiri T, et al. EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Cancer Sci. 2006;97:1211-6 pubmed
    ..analysis for ephrin ligand family members indicated the coexistence of ephrinA3 ligand in PDAC cells with EphA4 receptor, and knockdown of ephrinA3 by siRNA also attenuated PDAC cell viability...
  4. Eberhart J, Swartz M, Koblar S, Pasquale E, Krull C. EphA4 constitutes a population-specific guidance cue for motor neurons. Dev Biol. 2002;247:89-101 pubmed
    ..We show that ectopic expression of EphA4 receptor tyrosine kinase alters the trajectories of a specific population of motor axons in the avian hindlimb...
  5. Holmberg J, Frisen J. Ephrins are not only unattractive. Trends Neurosci. 2002;25:239-43 pubmed
    ..As numerous studies suggest functions more akin to adhesion or attraction than to repulsion, increasing attention is now being paid to the intracellular mechanisms that might explain this duality. ..
  6. Canty A, Greferath U, Turnley A, Murphy M. Eph tyrosine kinase receptor EphA4 is required for the topographic mapping of the corticospinal tract. Proc Natl Acad Sci U S A. 2006;103:15629-34 pubmed
    ..Together, these findings suggest that EphA4 regulates topographic mapping of the CST by controlling the branching of CST axons in the spinal cord. ..
  7. Walkenhorst J, Dütting D, Handwerker C, Huai J, Tanaka H, Drescher U. The EphA4 receptor tyrosine kinase is necessary for the guidance of nasal retinal ganglion cell axons in vitro. Mol Cell Neurosci. 2000;16:365-75 pubmed
    ..The results of these in vitro experiments suggest that EphA4 is crucially involved in the repulsive guidance of nasal but not of temporal axons. ..
  8. Richter M, Murai K, Bourgin C, Pak D, Pasquale E. The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci. 2007;27:14205-15 pubmed
    ..We have identified a novel interaction between the C terminus of the EphA4 receptor and the PDZ domain of the GTPase-activating protein spine-associated RapGAP (SPAR)...
  9. Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci U S A. 1998;95:13248-53 pubmed
    ..These results demonstrate a critical role for EphA4 in establishing the corticospinal projection. ..
  10. Qin H, Shi J, Noberini R, Pasquale E, Song J. Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor. J Biol Chem. 2008;283:29473-84 pubmed publisher
    ..The EphA4 receptor plays important roles in the inhibition of the regeneration of injured axons, synaptic plasticity, platelet ..
  11. Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, Cosford N, et al. Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem. 2008;283:29461-72 pubmed publisher
    ..throughput screen to search for small molecules that inhibit ligand binding to the extracellular domain of the EphA4 receptor. This yielded a 2,5-dimethylpyrrolyl benzoic acid derivative able to inhibit the interaction of EphA4 with a ..
  12. Fukai J, Yokote H, Yamanaka R, Arao T, Nishio K, Itakura T. EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. Mol Cancer Ther. 2008;7:2768-78 pubmed publisher
    ..Thus, our results indicate that EphA4 plays an important role in malignant phenotypes of glioblastoma by enhancing cell proliferation and migration through accelerating a canonical FGFR signaling pathway. ..
  13. Ellis C, Kasmi F, Ganju P, Walls E, Panayotou G, Reith A. A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene. 1996;12:1727-36 pubmed
  14. Irving C, Nieto M, Dasgupta R, Charnay P, Wilkinson D. Progressive spatial restriction of Sek-1 and Krox-20 gene expression during hindbrain segmentation. Dev Biol. 1996;173:26-38 pubmed
    ..We propose that the establishment and maintenance of these segmental domains may involve both a dynamic regulation of r3/r5 identity and the restriction of cell movement across rhombomere boundaries. ..
  15. Fu W, Chen Y, Sahin M, Zhao X, Shi L, Bikoff J, et al. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci. 2007;10:67-76 pubmed
    ..These findings suggest that ephrin-A1 promotes EphA4-dependent spine retraction through the activation of Cdk5 and ephexin1, which in turn modulates actin cytoskeletal dynamics. ..
  16. Warner N, Wybenga Groot L, Pawson T. Analysis of EphA4 receptor tyrosine kinase substrate specificity using peptide-based arrays. FEBS J. 2008;275:2561-73 pubmed publisher
    ..In the present study, we explored the substrate specificity of the EphA4 receptor tyrosine kinase using peptide arrays...
  17. Park E, Warner N, Bong Y, Stapleton D, Maeda R, Pawson T, et al. Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Mol Biol Cell. 2004;15:1647-55 pubmed
    ..contributions of specific structural motifs within Eph receptors, wild-type or mutant forms of the EphA4 receptor were ectopically expressed in developing Xenopus embryos...
  18. Singla N, Goldgur Y, Xu K, Paavilainen S, Nikolov D, Himanen J. Crystal structure of the ligand-binding domain of the promiscuous EphA4 receptor reveals two distinct conformations. Biochem Biophys Res Commun. 2010;399:555-9 pubmed publisher
    ..Our results suggest that the ligand promiscuity of the Ephs is directly correlated with the structural flexibility of the ligand-binding surface of the receptor. ..
  19. Murai K, Nguyen L, Irie F, Yamaguchi Y, Pasquale E. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci. 2003;6:153-60 pubmed
    ..Here we describe a repulsive interaction that regulates postsynaptic morphology through the EphA4 receptor tyrosine kinase and its ligand ephrin-A3...
  20. Theil T, Frain M, Gilardi Hebenstreit P, Flenniken A, Charnay P, Wilkinson D. Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20. Development. 1998;125:443-52 pubmed
    ..Together with evidence that Krox-20 regulates Hox gene expression, our findings reveal a mechanism by which the identity and movement of cells are coupled such that sharply restricted segmental domains are generated. ..
  21. Xu Q, Mellitzer G, Robinson V, Wilkinson D. In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature. 1999;399:267-71 pubmed
    ..These data implicate Eph receptors and ephrins in the segmental restriction of cell intermingling. ..
  22. Xu Q, Mellitzer G, Wilkinson D. Roles of Eph receptors and ephrins in segmental patterning. Philos Trans R Soc Lond B Biol Sci. 2000;355:993-1002 pubmed
    ..Eph receptors and ephrins have thus emerged as key regulators that, in parallel with cell adhesion molecules, underlie the establishment and maintenance of patterns of cellular organization. ..
  23. Ni X, Richmond H, Liao X, Decker W, Shiue L, Shpall E, et al. Induction of T-cell responses against cutaneous T-cell lymphomas ex vivo by autologous dendritic cells transfected with amplified tumor mRNA. J Invest Dermatol. 2008;128:2631-9 pubmed publisher
    ..These data support the concept of using tumor mRNA for a vaccine strategy that requires small amounts of tumor cells without need for specific antigens in patients with SzS. ..
  24. Goldshmit Y, Galea M, Wise G, Bartlett P, Turnley A. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci. 2004;24:10064-73 pubmed
    ..Thus, EphA4 regulates two important features of spinal cord injury, axonal inhibition, and astrocytic gliosis. ..
  25. Bouvier D, Tremblay M, Riad M, Corera A, Gingras D, Horn K, et al. EphA4 is localized in clathrin-coated and synaptic vesicles in adult mouse brain. J Neurochem. 2010;113:153-65 pubmed publisher
    ..This trafficking itinerary may serve to regulate the levels of EphA4 in the synaptic plasma membrane and thereby modulate signaling events that contribute to synaptic plasticity. ..
  26. Ohta K, Nakamura M, Hirokawa K, Tanaka S, Iwama A, Suda T, et al. The receptor tyrosine kinase, Cek8, is transiently expressed on subtypes of motoneurons in the spinal cord during development. Mech Dev. 1996;54:59-69 pubmed
    ..The unique expression of Cek8 suggests its involvement in cellular survival or cell-cell interactions for specific subpopulations of developing motoneurons. ..
  27. Lundfald L, Restrepo C, Butt S, Peng C, Droho S, Endo T, et al. Phenotype of V2-derived interneurons and their relationship to the axon guidance molecule EphA4 in the developing mouse spinal cord. Eur J Neurosci. 2007;26:2989-3002 pubmed
    ..Together, these findings enable a better interpretation of neural networks underlying locomotion, and open up the search for as yet unknown components of the mammalian central pattern generator. ..
  28. Schulte D, Cepko C. Two homeobox genes define the domain of EphA3 expression in the developing chick retina. Development. 2000;127:5033-45 pubmed
    ..They further suggest that the control of topographic specificity along the retinal nasal-temporal axis is split into several independent pathways already at a very early time in development. ..
  29. Cheng N, Brantley D, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev. 2002;13:75-85 pubmed
    ..This review will focus on the relevance of Eph receptor signaling in embryonic and adult neovascularization, and possible contributions to tumor growth and metastasis. ..
  30. Yue Y, Chen Z, Gale N, Blair Flynn J, Hu T, Yue X, et al. Mistargeting hippocampal axons by expression of a truncated Eph receptor. Proc Natl Acad Sci U S A. 2002;99:10777-82 pubmed
    ..Our observations provide strong support for a critical role of Eph family guidance factors in regulating ontogeny of hippocampal projections. ..
  31. Coonan J, Bartlett P, Galea M. Role of EphA4 in defining the position of a motoneuron pool within the spinal cord. J Comp Neurol. 2003;458:98-111 pubmed
    ..These observations suggest an important role for EphA4 in regulating the position of a specific motoneuron pool within the spinal cord. ..
  32. Bothe I, Dietrich S. The molecular setup of the avian head mesoderm and its implication for craniofacial myogenesis. Dev Dyn. 2006;235:2845-60 pubmed
    ..These factors show anteroposteriorly and dorsoventrally regionalised but overlapping expression. Notably, expression extends into the areas that actively contribute to the heart, overlapping with the expression of cardiac markers. ..
  33. Cruz Orengo L, Figueroa J, Velazquez I, Torrado A, Ortíz C, Hernandez C, et al. Blocking EphA4 upregulation after spinal cord injury results in enhanced chronic pain. Exp Neurol. 2006;202:421-33 pubmed
    ..One member of this family, the EphA4 receptor, coordinates appropriate corticospinal fibers projections during early development and is expressed in spinal ..
  34. Santiago A, Erickson C. Ephrin-B ligands play a dual role in the control of neural crest cell migration. Development. 2002;129:3621-32 pubmed
  35. Shi L, Fu W, Hung K, Porchetta C, Hall C, Fu A, et al. Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc Natl Acad Sci U S A. 2007;104:16347-52 pubmed
    ..Our findings have therefore identified a new alpha2-chimaerin-dependent signaling mechanism through which EphA4 transduces its signals to the actin cytoskeleton and modulates growth cone morphology. ..
  36. Rogers J, Ciossek T, Menzel P, Pasquale E. Eph receptors and ephrins demarcate cerebellar lobules before and during their formation. Mech Dev. 1999;87:119-28 pubmed
    ..These expression patterns define previously unknown developmental units and suggest that Eph family proteins may contribute to cerebellar morphogenesis. ..
  37. Klein R. Topography in hippocampal mossy fiber plasticity. Neuron. 2010;65:580-2 pubmed publisher
    ..In this issue of Neuron, Galimberti et al. demonstrate that mossy fibers of the rodent hippocampus exhibit prominent structural plasticity according to a novel topographic rule, in a process requiring the EphA4 receptor tyrosine kinase.
  38. Hirano S, Tanaka H, Ohta K, Norita M, Hoshino K, Meguro R, et al. Normal ontogenic observations on the expression of Eph receptor tyrosine kinase, Cek8, in chick embryos. Anat Embryol (Berl). 1998;197:187-97 pubmed
    ..Consequently, it appears that Cek8 plays an integral role in the developmental events leading to the formation of a wide--though not inclusive--variety of tissues and organ systems. ..
  39. Soans C, Holash J, Pavlova Y, Pasquale E. Developmental expression and distinctive tyrosine phosphorylation of the Eph-related receptor tyrosine kinase Cek9. J Cell Biol. 1996;135:781-95 pubmed
    ..Since autophosphorylation of receptor protein-tyrosine kinases typically correlates with increased enzymatic activity, this suggests that Cek9 plays an active role in embryonic signal transduction pathways. ..
  40. Filosa A, Paixão S, Honsek S, Carmona M, Becker L, Feddersen B, et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat Neurosci. 2009;12:1285-92 pubmed publisher
    ..These results suggest that EphA4/ephrin-A3 signaling is a critical mechanism for astrocytes to regulate synaptic function and plasticity. ..
  41. Fabes J, Anderson P, Brennan C, Bolsover S. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur J Neurosci. 2007;26:2496-505 pubmed
    ..These results suggest that blocking EphA4 is likely to contribute to a future successful clinical treatment for spinal cord injury. ..
  42. Tremblay M, Riad M, Bouvier D, Murai K, Pasquale E, Descarries L, et al. Localization of EphA4 in axon terminals and dendritic spines of adult rat hippocampus. J Comp Neurol. 2007;501:691-702 pubmed
    ..The dual preferential labeling of EphA4 on pre- or postsynaptic specializations of excitatory synapses in adult rat hippocampus is consistent with roles for this receptor in synaptic plasticity and LTP. ..
  43. Shin J, Gu C, Kim J, Park S. Transient activation of the MAP kinase signaling pathway by the forward signaling of EphA4 in PC12 cells. BMB Rep. 2008;41:479-84 pubmed
    ..Importantly, we found that the EphA4 receptor is rapidly internalized by endocytosis upon engagement of ephrin-A5, leading to a subsequent reduction in the ..
  44. Pickles J, van Heumen W. The expression of messenger RNAs coding for growth factors, their receptors, and eph-class receptor tyrosine kinases in normal and ototoxically damaged chick cochleae. Dev Neurosci. 1997;19:476-87 pubmed
    ..The eph-class receptor tyrosine kinase CEK10 may be involved in cell interactions in the cochlear sensory epithelium, while CEK4 and CEK8 may play a role in the cochlear innervation. ..
  45. North H, Karim A, Jacquin M, Donoghue M. EphA4 is necessary for spatially selective peripheral somatosensory topography. Dev Dyn. 2010;239:630-8 pubmed publisher
    ..EphA4's selective effect on a subset of whiskers implicates cell-based signaling in the establishment of position-dependent connectivity and topography in the peripheral somatosensory system. ..
  46. Takemoto M, Fukuda T, Sonoda R, Murakami F, Tanaka H, Yamamoto N. Ephrin-B3-EphA4 interactions regulate the growth of specific thalamocortical axon populations in vitro. Eur J Neurosci. 2002;16:1168-72 pubmed
    ..Axonal growth was inhibited for cells from the lateral thalamus but not from the medial thalamus. These results suggest that ephrin-B3 contributes to regional specificity by suppressing axonal growth of lateral thalamic neurons. ..
  47. Sela Donenfeld D, Kayam G, Wilkinson D. Boundary cells regulate a switch in the expression of FGF3 in hindbrain rhombomeres. BMC Dev Biol. 2009;9:16 pubmed publisher
    ..We show that chick embryos that lack boundary cells due to overexpression of truncated EphA4 receptor in the hindbrain have continued segmental expression of FGF3 at stages when it is normally restricted to ..
  48. Cheng H, Flanagan J. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell. 1994;79:157-68 pubmed
    ..Its sequence is homologous with B61, a ligand for the Eck kinase, defining a family of related ligands. The expression domains of ELF-1, Mek4 and Sek indicate potential roles in embryonic patterning. ..
  49. Yokote H, Fujita K, Jing X, Sawada T, Liang S, Yao L, et al. Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains. Proc Natl Acad Sci U S A. 2005;102:18866-71 pubmed
  50. Mühleisen T, Agoston Z, Schulte D. Retroviral misexpression of cVax disturbs retinal ganglion cell axon fasciculation and intraretinal pathfinding in vivo and guidance of nasal ganglion cell axons in vivo. Dev Biol. 2006;297:59-73 pubmed
  51. Murai K, Pasquale E. Neuroscience. Axons seek neighborly advice. Science. 2008;320:185-6 pubmed publisher
  52. Swartz M, Eberhart J, Pasquale E, Krull C. EphA4/ephrin-A5 interactions in muscle precursor cell migration in the avian forelimb. Development. 2001;128:4669-80 pubmed
    ..We have examined the distribution of members of the Eph family during muscle precursor cell development. The EphA4 receptor tyrosine kinase and its ligand, ephrin-A5, are expressed by muscle precursor cells and forelimb mesoderm in ..
  53. Tremblay M, Riad M, Chierzi S, Murai K, Pasquale E, Doucet G. Developmental course of EphA4 cellular and subcellular localization in the postnatal rat hippocampus. J Comp Neurol. 2009;512:798-813 pubmed publisher
    From embryonic development to adulthood, the EphA4 receptor and several of its ephrin-A or -B ligands are expressed in the hippocampus, where they presumably play distinct roles at different developmental stages...