Erythropoietin-Producing Human Hepatocellular Carcinoma (EphA1)

  • Christopher Medway
  • Anne Braae
  • Kevin Morgan


Eph-like receptors belong to the receptor tyrosine kinase family and are divided into two classes, A and B, based on their extracellular domains and the ephrin ligands that they bind. Eph signalling is complex as the two classes of receptors can interact to form functional “clusters” and the receptors themselves are capable of signalling. EphA1 is expressed in multiple tissues and is involved in cell adhesion and organisation of a range of developmental and physiological processes. In the CNS, EphA1 is involved in neural development, synapse plasticity and dendritic spine morphogenesis, suggesting that these receptors may be important as modifiers of neurodegenerative disease. A polymorphism (rs11767557) 3,154 bp upstream of EPHA1 has been significantly associated with Alzheimer’s disease in Caucasian cohorts; however, the functional variant remains unknown. Ephrin receptor signalling operates on known AD pathology pathways. Some ephrin receptors require processing by γ–secretase, which has previously been linked to AD. Furthermore, the role of ephrin receptors in neurodevelopment and spine morphology in AD areas of the brain suggests that differences in neural circuitry may be at fault.


Focal Adhesion Kinase Superior Colliculus EphA Receptor Spine Morphology Neural Stem Cell Differentiation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987) A novel putative tyrosine kinase receptor encoded by the eph gene. Science (New York, NY) 238:1717–1720CrossRefGoogle Scholar
  2. 2.
    Maru Y, Hirai H, Yoshida MC, Takaku F (1988) Evolution, expression, and chromosomal location of a novel receptor tyrosine kinase gene, eph. Mol Cell Biol 8:3770–3776PubMedGoogle Scholar
  3. 3.
    Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90:403–404CrossRefGoogle Scholar
  4. 4.
    Wilkinson DG (2001) Multiple roles of EPH receptors and ephrins in neural development. Nature reviews. Neuroscience 2:155–164PubMedGoogle Scholar
  5. 5.
    Coulthard MG et al (2001) Characterization of the Epha1 receptor tyrosine kinase: expression in epithelial tissues. Growth Factors (Chur, Switzerland) 18:303–317CrossRefGoogle Scholar
  6. 6.
    Hafner C et al (2004) Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem 50:490–499PubMedCrossRefGoogle Scholar
  7. 7.
    Dong Y et al (2009) Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol 22:151–160PubMedCrossRefGoogle Scholar
  8. 8.
    Triplett JW, Feldheim DA (2012) Eph and ephrin signaling in the formation of topographic maps. Semin Cell Dev Biol 23:7–15PubMedCrossRefGoogle Scholar
  9. 9.
    Hruska M, Dalva MB (2012) Ephrin regulation of synapse formation, function and plasticity. Mol Cell Neurosci 50:35–44PubMedCrossRefGoogle Scholar
  10. 10.
    Chen Y, Fu AKY, Ip NY (2012) Eph receptors at synapses: implications in neurodegenerative diseases. Cell Signal 24:606–611PubMedCrossRefGoogle Scholar
  11. 11.
    Kullander K, Klein R (2002) Mechanisms and functions of Eph and ephrin signalling. Nature reviews. Mol Cell Biol 3:475–486Google Scholar
  12. 12.
    Gale NW et al (1996) Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17:9–19PubMedCrossRefGoogle Scholar
  13. 13.
    Brückner K, Pasquale EB, Klein R (1997) Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science (New York, NY) 275:1640–1643CrossRefGoogle Scholar
  14. 14.
    Janes PW et al (2011) Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors. J Cell Biol 195:1033–1045PubMedCrossRefGoogle Scholar
  15. 15.
    Holland SJ et al (1996) Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383:722–725PubMedCrossRefGoogle Scholar
  16. 16.
    Davy A et al (1999) Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Gene Dev 13:3125–3135PubMedCrossRefGoogle Scholar
  17. 17.
    San Miguel S et al (2011) Ephrin reverse signaling controls palate fusion via a PI3 kinase-­dependent mechanism. Dev Dyn 240:357–364PubMedCrossRefGoogle Scholar
  18. 18.
    Miao H, Wang B (2012) EphA receptor signaling-complexity and emerging themes. Semin Cell Dev Biol 23:16–25PubMedCrossRefGoogle Scholar
  19. 19.
    Yamazaki T et al (2009) EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci 122:243–255PubMedCrossRefGoogle Scholar
  20. 20.
    Miao H, Burnett E, Kinch M, Simon E, Wang B (2000) Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2:62–69PubMedCrossRefGoogle Scholar
  21. 21.
    Deroanne C, Vouret-Craviari V, Wang B, Pouysségur J (2003) EphrinA1 inactivates integrin-­mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J Cell Sci 116:1367–1376PubMedCrossRefGoogle Scholar
  22. 22.
    Bourgin C, Murai KK, Richter M, Pasquale EB (2007) The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol 178:1295–1307PubMedCrossRefGoogle Scholar
  23. 23.
    Huai J, Drescher U (2001) An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein. J Biol Chem 276:6689–6694PubMedCrossRefGoogle Scholar
  24. 24.
    Lai K-O, Ip NY (2009) Synapse development and plasticity: roles of ephrin/Eph receptor signaling. Curr Opin Neurobiol 19:275–283PubMedCrossRefGoogle Scholar
  25. 25.
    Nie D et al (2010) Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat Neurosci 13:163–172PubMedCrossRefGoogle Scholar
  26. 26.
    Cheng HJ, Nakamoto M, Bergemann AD, Flanagan JG (1995) Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82:371–381PubMedCrossRefGoogle Scholar
  27. 27.
    Klein R (2009) Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat Neurosci 12:15–20PubMedCrossRefGoogle Scholar
  28. 28.
    Henkemeyer M, Itkis OS, Ngo M, Hickmott PW, Ethell IM (2003) Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol 163:1313–1326PubMedCrossRefGoogle Scholar
  29. 29.
    Kayser MS, Nolt MJ, Dalva MB (2008) EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59:56–69PubMedCrossRefGoogle Scholar
  30. 30.
    Moeller ML, Shi Y, Reichardt LF, Ethell IM (2006) EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation. J Biol Chem 281:1587–1598PubMedCrossRefGoogle Scholar
  31. 31.
    McClelland AC, Hruska M, Coenen AJ, Henkemeyer M, Dalva MB (2010) Trans-synaptic EphB2-ephrin-B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling. Proc Natl Acad Sci U S A 107:8830–8835PubMedCrossRefGoogle Scholar
  32. 32.
    Torres R et al (1998) PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21:1453–1463PubMedCrossRefGoogle Scholar
  33. 33.
    Armstrong JN et al (2006) B-ephrin reverse signaling is required for NMDA-independent long-term potentiation of mossy fibers in the hippocampus. J Neurosci 26:3474–3481PubMedCrossRefGoogle Scholar
  34. 34.
    Essmann CL et al (2008) Serine phosphorylation of ephrinB2 regulates trafficking of synaptic AMPA receptors. Nat Neurosci 11:1035–1043PubMedCrossRefGoogle Scholar
  35. 35.
    Xu N-J, Sun S, Gibson JR, Henkemeyer M (2011) A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses. Nat Neurosci 14:1421–1429PubMedCrossRefGoogle Scholar
  36. 36.
    Segura I, Essmann CL, Weinges S, Acker-Palmer A (2007) Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation. Nat Neurosci 10:301–310PubMedCrossRefGoogle Scholar
  37. 37.
    Antion MD, Christie LA, Bond AM, Dalva MB, Contractor A (2010) Ephrin-B3 regulates glutamate receptor signaling at hippocampal synapses. Mol Cell Neurosci 45:378–388PubMedCrossRefGoogle Scholar
  38. 38.
    Nakamura-Hirota T, Kadoyama K, Takano M, Otani M, Matsuyama S (2012) The expression changes of EphA3 receptor during synaptic plasticity in mouse hippocampus through activation of nicotinic acetylcholine receptor. Neuroreport 23:746–751PubMedCrossRefGoogle Scholar
  39. 39.
    Filosa A et al (2009) Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nat Neurosci 12:1285–1292PubMedCrossRefGoogle Scholar
  40. 40.
    Murai KK, Nguyen LN, Irie F, Yamaguchi Y, Pasquale EB (2003) Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci 6:153–160PubMedCrossRefGoogle Scholar
  41. 41.
    Fu W-Y et al (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67–76PubMedCrossRefGoogle Scholar
  42. 42.
    Carmona MA, Murai KK, Wang L, Roberts AJ, Pasquale EB (2009) Glial ephrin-A3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc Natl Acad Sci U S A 106:12524–12529PubMedCrossRefGoogle Scholar
  43. 43.
    Khodosevich K, Watanabe Y, Monyer H (2011) EphA4 preserves postnatal and adult neural stem cells in an undifferentiated state in vivo. J Cell Sci 124:1268–1279PubMedCrossRefGoogle Scholar
  44. 44.
    Owshalimpur D, Kelley MJ (1999) Genomic structure of the EPHA1 receptor tyrosine kinase gene. Mol Cell Probes 13:169–173PubMedCrossRefGoogle Scholar
  45. 45.
    Hollingworth P et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43:429–435PubMedCrossRefGoogle Scholar
  46. 46.
    Naj AC et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43:436–441PubMedCrossRefGoogle Scholar
  47. 47.
    Carrasquillo MM et al (2011) Replication of EPHA1 and CD33 associations with late-onset Alzheimer’s disease: a multi-centre case-control study. Mol Neurodegeneration 6:54CrossRefGoogle Scholar
  48. 48.
    1000 Genomes Project Consortium (2010) A map of human genome variation from population-­scale sequencing. Nature 467:1061–1073CrossRefGoogle Scholar
  49. 49.
    Johnson AD et al (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics (Oxford, England) 24:2938–2939CrossRefGoogle Scholar
  50. 50.
    Cissé M et al (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469:47–52PubMedCrossRefGoogle Scholar
  51. 51.
    Moreno-Flores MT, Martín-Aparicio E, Avila J, Díaz-Nido J, Wandosell F (2002) Ephrin-B1 promotes dendrite outgrowth on cerebellar granule neurons. Mol Cell Neurosci 20:429–446PubMedCrossRefGoogle Scholar
  52. 52.
    Tomita T, Tanaka S, Morohashi Y, Iwatsubo T (2006) Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegeneration 1:2CrossRefGoogle Scholar
  53. 53.
    Inoue E et al (2009) Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. J Cell Biol 185:551–564PubMedCrossRefGoogle Scholar
  54. 54.
    Xu J, Litterst C, Georgakopoulos A, Zaganas I, Robakis NK (2009) Peptide EphB2/CTF2 generated by the gamma-secretase processing of EphB2 receptor promotes tyrosine phosphorylation and cell surface localization of N-methyl-d-aspartate receptors. J Biol Chem 284:27220–27228PubMedCrossRefGoogle Scholar
  55. 55.
    Yoo S, Shin J, Park S (2010) EphA8-ephrinA5 signaling and clathrin-mediated endocytosis is regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor. Mol Cell 29:603–609CrossRefGoogle Scholar
  56. 56.
    Irie F, Okuno M, Pasquale EB, Yamaguchi Y (2005) EphrinB-EphB signalling regulates clathrin-­mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat Cell Biol 7:501–509PubMedCrossRefGoogle Scholar
  57. 57.
    Morgan K (2011) The three new pathways leading to Alzheimer’s disease. Neuropathol Appl Neurobiol 37:353–357PubMedCrossRefGoogle Scholar
  58. 58.
    Simón AM et al (2009) Early changes in hippocampal Eph receptors precede the onset of memory decline in mouse models of Alzheimer’s disease. J Alzheim Dis 17:773–786Google Scholar
  59. 59.
    Litterst C et al (2007) Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-­processing pathways of EphB2 receptor. J Biol Chem 282:16155–16163PubMedCrossRefGoogle Scholar
  60. 60.
    Barthet G et al (2012) Presenilin mediates neuroprotective functions of ephrinB and brain-­derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging. doi: 10.1016/j.neurobiolaging.2012.02.024 PubMedGoogle Scholar
  61. 61.
    Van Hoecke A et al (2012) EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. doi: 10.1038/nm.2901 PubMedGoogle Scholar
  62. 62.
    Consortium TU (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40:D71–D75CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Human Genetics, School of Molecular Medical Sciences, Queen’s Medical CentreUniversity of NottinghamNottinghamUK

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