eph family receptors


Summary: A large family of receptor protein-tyrosine kinases that are structurally-related. The name of this family of proteins derives from original protein Eph (now called the EPHA1 RECEPTOR), which was named after the cell line it was first discovered in: Erythropoietin-Producing human Hepatocellular carcinoma cell line. Members of this family have been implicated in regulation of cell-cell interactions involved in nervous system patterning and development.

Top Publications

  1. Batlle E, Henderson J, Beghtel H, van den Born M, Sancho E, Huls G, et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell. 2002;111:251-63 pubmed
    ..We conclude 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...
  2. Penzes P, Beeser A, Chernoff J, Schiller M, Eipper B, Mains R, et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron. 2003;37:263-74 pubmed
    ..This novel signal transduction pathway may be critical for the regulation of the actin cytoskeleton controlling spine morphogenesis during development and plasticity. ..
  3. Davy A, Soriano P. Ephrin signaling in vivo: look both ways. Dev Dyn. 2005;232:1-10 pubmed
  4. Konstantinova I, Nikolova G, Ohara Imaizumi M, Meda P, Kucera T, Zarbalis K, et al. EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets. Cell. 2007;129:359-70 pubmed
    ..Thus, we explain how beta cell communication in pancreatic islets conversely affects basal and glucose-stimulated insulin secretion to improve glucose homeostasis. ..
  5. Torii M, Hashimoto Torii K, Levitt P, Rakic P. Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature. 2009;461:524-8 pubmed publisher
  6. Surawska H, Ma P, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev. 2004;15:419-33 pubmed
    ..This review emphasizes the biology of Eph/ephrin as well as the potential for novel targeted therapy through this pathway. ..
  7. Durbin L, Brennan C, Shiomi K, Cooke J, Barrios A, Shanmugalingam S, et al. Eph signaling is required for segmentation and differentiation of the somites. Genes Dev. 1998;12:3096-109 pubmed
    ..We suggest that Eph signaling has a key role in the translation of the patterning of presomitic mesoderm into somites. ..
  8. Pasquale E. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133:38-52 pubmed publisher
  9. Cortina C, Palomo Ponce S, Iglesias M, Fernández Masip J, Vivancos A, Whissell G, et al. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet. 2007;39:1376-83 pubmed
    ..Our results indicate that CRC cells must silence EphB expression to avoid repulsive interactions imposed by normal ephrin-B1-expressing intestinal cells at the onset of tumorigenesis. ..

More Information


  1. Schmitt A, Shi J, Wolf A, Lu C, King L, Zou Y. Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature. 2006;439:31-7 pubmed
    ..Therefore, a classical morphogen, Wnt3, acting as an axon guidance molecule, plays a role in retinotectal mapping along the medial-lateral axis, counterbalancing the medial-directed EphrinB1-EphB activity. ..
  2. Brantley Sieders D, Fang W, Hicks D, Zhuang G, Shyr Y, Chen J. Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J. 2005;19:1884-6 pubmed
    ..These data suggest that host EphA2 receptor tyrosine kinase function is required in the tumor microenvironment for tumor angiogenesis and metastatic progression. ..
  3. Huberman A, Murray K, Warland D, Feldheim D, Chapman B. Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus. Nat Neurosci. 2005;8:1013-21 pubmed
  4. Batlle E, Bacani J, Begthel H, Jonkheer S, Jonkeer S, Gregorieff A, et al. EphB receptor activity suppresses colorectal cancer progression. Nature. 2005;435:1126-30 pubmed
    ..Our data demonstrate that loss of EphB expression represents a critical step in colorectal cancer progression. ..
  5. Depaepe V, Suarez Gonzalez N, Dufour A, Passante L, Gorski J, Jones K, et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature. 2005;435:1244-50 pubmed
    ..Together, these results identify ephrin/Eph signalling as a physiological trigger for apoptosis that can alter brain size and shape by regulating the number of neural progenitors. ..
  6. Brantley Sieders D, Schmidt S, Parker M, Chen J. Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des. 2004;10:3431-42 pubmed
    ..This review will focus on recent advances in dissecting the role of Eph RTKs in tumor cells, tumor angiogenesis, and possible contribution to trafficking of inflammatory cells in cancer. ..
  7. Yamaguchi Y, Pasquale E. Eph receptors in the adult brain. Curr Opin Neurobiol. 2004;14:288-96 pubmed
  8. Cheng N, Brantley D, Fang W, Liu H, Fanslow W, Cerretti D, et al. Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors. Neoplasia. 2003;5:445-56 pubmed
    ..These data provide functional evidence for EphA class receptor regulation of VEGF-dependent tumor angiogenesis, suggesting that the EphA signaling pathway may represent an attractive novel target for antiangiogenic therapy in cancer. ..
  9. Cowan C, Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature. 2001;413:174-9 pubmed
    ..These data provide a biochemical pathway whereby cytoskeletal regulators are recruited to Eph-ephrin bidirectional signalling complexes. ..
  10. Grunwald I, Korte M, Adelmann G, Plueck A, Kullander K, Adams R, et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nat Neurosci. 2004;7:33-40 pubmed
    ..This work raises the intriguing possibility that depending on the type of synapse, Eph/ephrins can be involved in activity-dependent plasticity in converse ways, with ephrinBs on the pre- or the postsynaptic side. ..
  11. Drescher U. Eph family functions from an evolutionary perspective. Curr Opin Genet Dev. 2002;12:397-402 pubmed
    ..The structural analysis of Eph/ephrin crystals is providing hints for the existence of Eph and ephrin folds in plants and suggests a mechanism for triggering bi-directional signalling. ..
  12. Calò L, Cinque C, Patanè M, Schillaci D, Battaglia G, Melchiorri D, et al. Interaction between ephrins/Eph receptors and excitatory amino acid receptors: possible relevance in the regulation of synaptic plasticity and in the pathophysiology of neuronal degeneration. J Neurochem. 2006;98:1-10 pubmed
    ..This may stimulate the search for new drugs that might modulate excitatory synaptic transmission by interacting with the ephrin/Eph receptor system. ..
  13. Poliakov A, Cotrina M, Wilkinson D. Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell. 2004;7:465-80 pubmed
    ..This review will discuss biochemical mechanisms and developmental roles of the diverse cell responses controlled by Eph receptors and ephrins. ..
  14. Fox B, Kandpal R. Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun. 2004;318:882-92 pubmed
  15. Aoki M, Yamashita T, Tohyama M. EphA receptors direct the differentiation of mammalian neural precursor cells through a mitogen-activated protein kinase-dependent pathway. J Biol Chem. 2004;279:32643-50 pubmed
    ..Our results identify EphA receptors as positive regulators of the mitogen-activated protein kinase pathway that exerts neurogenesis of neural precursor cells from the developing central nervous system. ..
  16. Dalva M, Takasu M, Lin M, Shamah S, Hu L, Gale N, et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell. 2000;103:945-56 pubmed
    ..These findings indicate that EphrinB activation of EphB promotes an association of EphB with NMDA receptors that may be critical for synapse development or function. ..
  17. Murai K, Pasquale E. 'Eph'ective signaling: forward, reverse and crosstalk. J Cell Sci. 2003;116:2823-32 pubmed
    ..Deciphering the bi-directional pathways emanating from an Eph receptor-ephrin complex will not only help us to understand basic biological processes, but may also provide important insight into disease. ..
  18. 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
    ..Thus, our data support a model in which transient interactions between the ephrin-A3 ligand and the EphA4 receptor regulate the structure of excitatory synaptic connections through neuroglial cross-talk. ..
  19. Kania A, Jessell T. Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions. Neuron. 2003;38:581-96 pubmed
    ..These topographic projections are established, in part, through LIM homeodomain protein control of EphA receptors and ephrin-A ligands in motor neurons and limb mesenchymal cells. ..
  20. Battaglia A, Sehayek K, Grist J, McMahon S, Gavazzi I. EphB receptors and ephrin-B ligands regulate spinal sensory connectivity and modulate pain processing. Nat Neurosci. 2003;6:339-40 pubmed
  21. Arvanitis D, Davy A. Eph/ephrin signaling: networks. Genes Dev. 2008;22:416-29 pubmed publisher
    ..The complexity of Eph/ephrin function is discussed in terms of the pathways that regulate Eph/ephrin signaling and also the pathways that are regulated by Eph/ephrin signaling. ..
  22. Liebl D, Morris C, Henkemeyer M, Parada L. mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system. J Neurosci Res. 2003;71:7-22 pubmed
    ..These studies suggest additional potential roles for these molecules in the postnatal and adult CNS and will serve as a guide in the detailed evaluation of mutant mice. ..
  23. Shi W, Levine M. Ephrin signaling establishes asymmetric cell fates in an endomesoderm lineage of the Ciona embryo. Development. 2008;135:931-40 pubmed publisher
    ..These results extend recent observations regarding the role of Ephrin signaling in the establishment of asymmetric cell fates in the Ciona notochord and neural tube. ..
  24. Marquardt T, Shirasaki R, Ghosh S, Andrews S, Carter N, Hunter T, et al. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell. 2005;121:127-39 pubmed
  25. Mohamed A, Chin Sang I. Characterization of loss-of-function and gain-of-function Eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration. Dev Biol. 2006;290:164-76 pubmed
    ..The combination of loss-of-function and gain-of-function analyses suggests that the VAB-1 Eph RTK is required for targeting or limiting axons and neuronal cells to specific regions, perhaps by transducing a repellent or stop cue. ..
  26. Fox B, Tabone C, Kandpal R. Potential clinical relevance of Eph receptors and ephrin ligands expressed in prostate carcinoma cell lines. Biochem Biophys Res Commun. 2006;342:1263-72 pubmed
    ..The utility of methylation specific PCR to identify prostate tumor cells and the importance of specific Eph receptors and ephrin ligands in initiation and progression of prostate tumor are discussed. ..
  27. Pickles J, Claxton C, Van Heumen W. Complementary and layered expression of Ephs and ephrins in developing mouse inner ear. J Comp Neurol. 2002;449:207-16 pubmed
    ..The results suggest that the Eph system in the cochlea may have a role in maintaining cell segregation during phases of cochlear development. ..
  28. Salvucci O, De La Luz Sierra M, Martina J, McCormick P, Tosato G. EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood. 2006;108:2914-22 pubmed
  29. Hindges R, McLaughlin T, Genoud N, Henkemeyer M, O Leary D. EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron. 2002;35:475-87 pubmed
    ..Our data suggest that branches of EphB expressing axons are attracted medially by ephrin-B1, and provide molecular mechanisms for D-V mapping in visual centers. ..
  30. Feldheim D, Nakamoto M, Osterfield M, Gale N, DeChiara T, Rohatgi R, et al. Loss-of-function analysis of EphA receptors in retinotectal mapping. J Neurosci. 2004;24:2542-50 pubmed
  31. Cowan C, Henkemeyer M. Ephrins in reverse, park and drive. Trends Cell Biol. 2002;12:339-46 pubmed
  32. Zimmer M, Palmer A, Köhler J, Klein R. EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol. 2003;5:869-78 pubmed
    ..Here, we show a mechanism for the termination of adhesion and the promotion of cell repulsion after intercellular (trans) interaction between two transmembrane proteins. ..
  33. Koolpe M, Burgess R, Dail M, Pasquale E. EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J Biol Chem. 2005;280:17301-11 pubmed
    ..These peptides should be useful as selective inhibitors of the pathological activities of EphB receptors and as targeting agents for imaging probes and therapeutic drugs. ..
  34. Ricard J, Salinas J, Garcia L, Liebl D. EphrinB3 regulates cell proliferation and survival in adult neurogenesis. Mol Cell Neurosci. 2006;31:713-22 pubmed
    ..Together, our results suggest that ephrinB3 negatively regulates cell cycle progression and cell apoptosis in the adult subventricular zone. ..
  35. Kulkarni R, Kahn C. Ephs and ephrins keep pancreatic Beta cells connected. Cell. 2007;129:241-3 pubmed
    ..2007) show that the signaling proteins EphA and ephrin-A modulate insulin secretion, providing fresh insights into the functional significance of the clustering of beta cells, which occurs in islets. ..
  36. Munarini N, Jäger R, Abderhalden S, Zuercher G, Rohrbach V, Loercher S, et al. Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase. J Cell Sci. 2002;115:25-37 pubmed
    ..These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland. ..
  37. de Saint Vis B, Bouchet C, Gautier G, Valladeau J, Caux C, Garrone P. Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin. Blood. 2003;102:4431-40 pubmed
    ..As such, EphA2/ephrin-A3 interactions may play a role in the localization and network of Langerhans cells in the epithelium and in the regulation of their trafficking. ..
  38. Compagni A, Logan M, Klein R, Adams R. Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell. 2003;5:217-30 pubmed
    ..Our findings suggest that differential cell adhesion and sorting might be relevant for an unusual class of X-linked human genetic disorders, in which heterozygous females show more severe phenotypes than hemizygous males. ..
  39. Wu J, Luo H. Recent advances on T-cell regulation by receptor tyrosine kinases. Curr Opin Hematol. 2005;12:292-7 pubmed
    ..Multiple tissue-specific gene null mutations on Ephs or ephrins will likely reveal more interesting immune-related phenotypes. ..
  40. Gu J, Gu X. Natural history and functional divergence of protein tyrosine kinases. Gene. 2003;317:49-57 pubmed
    ..Our results show that site-specific shifted evolutionary rate (altered functional constraint) is a common pattern in PTK gene family evolution. ..
  41. Klein R. Eph/ephrin signaling in morphogenesis, neural development and plasticity. Curr Opin Cell Biol. 2004;16:580-9 pubmed
    ..Mechanistically, Eph-ephrin repulsive behavior appears to require ligand-receptor internalization and signaling to Rho GTPases. ..
  42. Takasu M, Dalva M, Zigmond R, Greenberg M. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science. 2002;295:491-5 pubmed
  43. Barrios A, Poole R, Durbin L, Brennan C, Holder N, Wilson S. Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis. Curr Biol. 2003;13:1571-82 pubmed
    ..We propose a new role for Eph receptors and Ephrins as intercellular signaling molecules that establish cell polarity during mesenchymal-to-epithelial transition of the paraxial mesoderm. ..
  44. Picco V, Hudson C, Yasuo H. Ephrin-Eph signalling drives the asymmetric division of notochord/neural precursors in Ciona embryos. Development. 2007;134:1491-7 pubmed
  45. 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
  46. 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. ..
  47. Prin F, Ng K, Thaker U, Drescher U, Guthrie S. Ephrin-As play a rhombomere-specific role in trigeminal motor axon projections in the chick embryo. Dev Biol. 2005;279:402-19 pubmed
    ..These findings indicate that ephrins and their Eph receptors play a role in trigeminal motor axon topographic mapping and in rhombomere 3-derived projections in particular. ..
  48. Chong S, Jiang Y. Off limits--integrins holding boundaries in somitogenesis. Trends Cell Biol. 2005;15:453-7 pubmed
    ..These studies shed light on components downstream of the periodic segmentation mechanism - the 'segmentation clock' - in somitogenesis. ..
  49. Tanaka M, Kamo T, Ota S, Sugimura H. Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion. EMBO J. 2003;22:847-58 pubmed
    ..We propose that Xdsh, which is expressed in various tissues, is involved in EphB and ephrin-B signaling related to regulation of cell repulsion via modification of RhoA activity. ..
  50. 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. ..
  51. Scales J, Winning R, Renaud C, Shea L, Sargent T. Novel members of the eph receptor tyrosine kinase subfamily expressed during Xenopus development. Oncogene. 1995;11:1745-52 pubmed
    ..The inability to unambiguously assign TCK and PL7a as Xenopus homologues of any previously identified eph RTK leads us to conclude that these cDNAs represent novel members of this family. ..
  52. Brisbin S, Liu J, Boudreau J, Peng J, Evangelista M, Chin Sang I. A role for C. elegans Eph RTK signaling in PTEN regulation. Dev Cell. 2009;17:459-69 pubmed publisher
    ..Possible implications for human cancers are discussed, based on the idea that mutually inhibitory interactions between PTEN and Eph RTKs may be conserved. ..
  53. Margolis S, Salogiannis J, Lipton D, Mandel Brehm C, Wills Z, Mardinly A, et al. EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010;143:442-55 pubmed publisher
    ..These findings suggest that aberrant EphB/Ephexin5 signaling during the development of synapses may contribute to the abnormal cognitive function that occurs in Angelman syndrome and, possibly, ASDs...