1932

Abstract

The rythropoietin-roducing epatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with eceptor-teracting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase–dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact–dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-011112-140226
2015-01-06
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/55/1/annurev-pharmtox-011112-140226.html?itemId=/content/journals/10.1146/annurev-pharmtox-011112-140226&mimeType=html&fmt=ahah

Literature Cited

  1. Pasquale EB. 1.  2005. Eph receptor signalling casts a wide net on cell behaviour. Nat. Rev. Mol. Cell Biol. 6:462–75 [Google Scholar]
  2. Pasquale EB. 2.  2008. Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52 [Google Scholar]
  3. Batlle E, Wilkinson DG. 3.  2012. Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis. Cold Spring Harb. Perspect. Biol. 4:a008227 [Google Scholar]
  4. Pasquale EB. 4.  2010. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat. Rev. Cancer 10:165–80 [Google Scholar]
  5. Goldshmit Y, McLenachan S, Turnley A. 5.  2006. Roles of Eph receptors and ephrins in the normal and damaged adult CNS. Brain Res. Rev. 52:327–45 [Google Scholar]
  6. Arvanitis DN, Davy A. 6.  2012. Regulation and misregulation of Eph/ephrin expression. Cell Adhes. Migr. 6:131–37 [Google Scholar]
  7. Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiainen M. 7.  et al. 2013. EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion. J. Cell Biol. 201:467–84 [Google Scholar]
  8. Lisabeth EM, Falivelli G, Pasquale EB. 8.  2013. Eph receptor signaling and ephrins. Cold Spring Harb. Perspect. Biol. 5:a009159 [Google Scholar]
  9. Pitulescu ME, Adams RH. 9.  2010. Eph/ephrin molecules—a hub for signaling and endocytosis. Genes Dev. 24:2480–92 [Google Scholar]
  10. Binda E, Visioli A, Giani F, Lamorte G, Copetti M. 10.  et al. 2012. The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell 22:765–80 [Google Scholar]
  11. Hwang YS, Lee HS, Kamata T, Mood K, Cho HJ. 11.  et al. 2013. The Smurf ubiquitin ligases regulate tissue separation via antagonistic interactions with ephrinB1. Genes Dev. 27:491–503 [Google Scholar]
  12. Choi KM, Park GL, Hwang KY, Lee JW, Ahn HJ. 12.  2013. Efficient siRNA delivery into tumor cells by p19-YSA fusion protein. Mol. Pharm. 10:763–73 [Google Scholar]
  13. Daar IO. 13.  2012. Non-SH2/PDZ reverse signaling by ephrins. Semin. Cell Dev. Biol. 23:65–74 [Google Scholar]
  14. Wykosky J, Debinski W. 14.  2008. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol. Cancer Res. 6:1795–806 [Google Scholar]
  15. Beauchamp A, Lively MO, Mintz A, Gibo D, Wykosky J, Debinski W. 15.  2012. EphrinA1 is released in three forms from cancer cells by matrix metalloproteases. Mol. Cell. Biol. 32:3253–64 [Google Scholar]
  16. Falivelli G, Lisabeth EM, Rubio de la Torre E, Perez-Tenorio G, Tosato G. 16.  et al. 2013. Attenuation of Eph receptor kinase activation in cancer cells by coexpressed ephrin ligands. PLOS ONE 8:e81445 [Google Scholar]
  17. Janes PW, Nievergall E, Lackmann M. 17.  2012. Concepts and consequences of Eph receptor clustering. Semin. Cell Dev. Biol. 23:43–50 [Google Scholar]
  18. Truitt L, Freywald A. 18.  2011. Dancing with the dead: Eph receptors and their kinase-null partners. Biochem. Cell Biol. 89:115–29 [Google Scholar]
  19. Gopal U, Bohonowych JE, Lema-Tome C, Liu A, Garrett-Mayer E. 19.  et al. 2011. A novel extracellular Hsp90 mediated co-receptor function for LRP1 regulates EphA2 dependent glioblastoma cell invasion. PLOS ONE 6:e17649 [Google Scholar]
  20. Argenzio E, Bange T, Oldrini B, Bianchi F, Peesari R. 20.  et al. 2011. Proteomic snapshot of the EGF-induced ubiquitin network. Mol. Syst. Biol. 7:462 [Google Scholar]
  21. Bouche E, Romero-Ortega MI, Henkemeyer M, Catchpole T, Leemhuis J. 21.  et al. 2013. Reelin induces EphB activation. Cell Res. 23:473–90 [Google Scholar]
  22. Miao H, Li DQ, Mukherjee A, Guo H, Petty A. 22.  et al. 2009. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16:9–20 [Google Scholar]
  23. Astin JW, Batson J, Kadir S, Charlet J, Persad RA. 23.  et al. 2010. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat. Cell Biol. 12:1194–204 [Google Scholar]
  24. Theus MH, Ricard J, Glass SJ, Travieso LG, Liebl DJ. 24.  2014. EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury. Cell Death Dis. 5:e1207 [Google Scholar]
  25. Bochenek ML, Dickinson S, Astin JW, Adams RH, Nobes CD. 25.  2010. Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J. Cell Sci. 123:1235–46 [Google Scholar]
  26. Senturk A, Pfennig S, Weiss A, Burk K, Acker-Palmer A. 26.  2011. Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature 472:356–60 [Google Scholar]
  27. Genet G, Guilbeau-Frugier C, Honton B, Dague E, Schneider MD. 27.  et al. 2012. Ephrin-B1 is a novel specific component of the lateral membrane of the cardiomyocyte and is essential for the stability of cardiac tissue architecture cohesion. Circ. Res. 110:688–700 [Google Scholar]
  28. Arvanitis D, Davy A. 28.  2008. Eph/ephrin signaling: networks. Genes Dev. 22:416–29 [Google Scholar]
  29. Hruska M, Dalva MB. 29.  2012. Ephrin regulation of synapse formation, function and plasticity. Mol. Cell Neurosci. 50:35–44 [Google Scholar]
  30. Du J, Fu C, Sretavan DW. 30.  2007. Eph/ephrin signaling as a potential therapeutic target after central nervous system injury. Curr. Pharm. Des. 13:2507–18 [Google Scholar]
  31. Vasileiou I, Adamakis I, Patsouris E, Theocharis S. 31.  2013. Ephrins and pain. Expert Opin. Ther. Targets 17:879–87 [Google Scholar]
  32. Funk SD, Orr AW. 32.  2013. Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis. Pharmacol. Res. 67:42–52 [Google Scholar]
  33. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM. 33.  et al. 2012. Eph/ephrin signaling in injury and inflammation. Am. J. Pathol. 181:1493–503 [Google Scholar]
  34. Sheffler-Collins SI, Dalva MB. 34.  2012. EphBs: an integral link between synaptic function and synaptopathies. Trends Neurosci. 35:293–304 [Google Scholar]
  35. Chen Y, Fu AK, Ip NY. 35.  2012. Eph receptors at synapses: implications in neurodegenerative diseases. Cell Signal. 24:606–11 [Google Scholar]
  36. Noberini R, Lamberto I, Pasquale EB. 36.  2012. Targeting Eph receptors with peptides and small molecules: progress and challenges. Semin. Cell Dev. Biol. 23:51–57 [Google Scholar]
  37. Tognolini M, Hassan-Mohamed I, Giorgio C, Zanotti I, Lodola A. 37.  2013. Therapeutic perspectives of Eph–ephrin system modulation. Drug Discov. Today 19:661–69 [Google Scholar]
  38. Harrison C. 38.  2014. Patents related to EPH receptors and ligands. Nat. Rev. Drug Discov. 13:13 [Google Scholar]
  39. Boyd AW, Bartlett PF, Lackmann M. 39.  2014. Therapeutic targeting of EPH receptors and their ligands. Nat. Rev. Drug Discov. 13:39–62 [Google Scholar]
  40. Conway A, Vazin T, Spelke DP, Rode NA, Healy KE. 40.  et al. 2013. Multivalent ligands control stem cell behaviour in vitro and in vivo. Nat. Nanotechnol. 8:831–38 [Google Scholar]
  41. Goldshmit Y, Spanevello MD, Tajouri S, Li L, Rogers F. 41.  et al. 2011. EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLOS ONE 6:e24636 [Google Scholar]
  42. Fabes J, Anderson P, Brennan C, Bolsover S. 42.  2007. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur. J. Neurosci. 26:2496–505 [Google Scholar]
  43. Spanevello MD, Tajouri SI, Mirciov C, Kurniawan N, Pearse MJ. 43.  et al. 2013. Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats. J. Neurotrauma 30:1023–34 [Google Scholar]
  44. Kempf A, Montani L, Petrinovic MM, Schroeter A, Weinmann O. 44.  et al. 2013. Upregulation of axon guidance molecules in the adult central nervous system of Nogo-A knockout mice restricts neuronal growth and regeneration. Eur. J. Neurosci. 38:3567–79 [Google Scholar]
  45. Munro KM, Perreau VM, Turnley AM. 45.  2012. Differential gene expression in the EphA4 knockout spinal cord and analysis of the inflammatory response following spinal cord injury. PLOS ONE 7:e37635 [Google Scholar]
  46. Duffy P, Wang X, Siegel CS, Tu N, Henkemeyer M. 46.  et al. 2012. Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury. Proc. Natl. Acad. Sci. USA 109:5063–68 [Google Scholar]
  47. Ren Z, Chen X, Yang J, Kress BT, Tong J. 47.  et al. 2013. Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter. Neuroscience 241:89–99 [Google Scholar]
  48. Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA. 48.  et al. 2012. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat. Med. 18:1418–22 [Google Scholar]
  49. Overman JJ, Clarkson AN, Wanner IB, Overman WT, Eckstein I. 49.  et al. 2012. A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc. Natl. Acad. Sci. USA 109:E2230–39 [Google Scholar]
  50. Lemmens R, Jaspers T, Robberecht W, Thijs VN. 50.  2013. Modifying expression of EphA4 and its downstream targets improves functional recovery after stroke. Hum. Mol. Genet. 22:2214–20 [Google Scholar]
  51. Cisse M, Halabisky B, Harris J, Devidze N, Dubal DB. 51.  et al. 2011. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469:47–52 [Google Scholar]
  52. Vargas LM, Leal N, Estrada LD, González A, Serrano F. 52.  et al. 2014. EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-beta oligomers. PLOS ONE 9:e92309 [Google Scholar]
  53. Fu AK, Hung KW, Huang H, Gu S, Shen Y. 53.  et al. 2014. Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 111:9959–64 [Google Scholar]
  54. Lai WB, Wang BJ, Hu MK, Hsu WM, Her GM, Liao YF. 54.  2014. Ligand-dependent activation of EphA4 signaling regulates the proteolysis of amyloid precursor protein through a Lyn-mediated pathway. Mol. Neurobiol. 49:1055–68 [Google Scholar]
  55. Matsui C, Inoue E, Kakita A, Arita K, Deguchi-Tawarada M. 55.  et al. 2012. Involvement of the γ-secretase-mediated EphA4 signaling pathway in synaptic pathogenesis of Alzheimer's disease. Brain Pathol. 22:776–87 [Google Scholar]
  56. Barthet G, Dunys J, Shao Z, Xuan Z, Ren Y. 56.  et al. 2013. 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 34:499–510 [Google Scholar]
  57. Schellenberg GD, Montine TJ. 57.  2012. The genetics and neuropathology of Alzheimer's disease. Acta Neuropathol. 124:305–23 [Google Scholar]
  58. Lin L, Lesnick TG, Maraganore DM, Isacson O. 58.  2009. Axon guidance and synaptic maintenance: preclinical markers for neurodegenerative disease and therapeutics. Trends Neurosci. 32:142–49 [Google Scholar]
  59. Jing X, Miwa H, Sawada T, Nakanishi I, Kondo T. 59.  et al. 2012. Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease. PLOS ONE 7:e32019 [Google Scholar]
  60. Cibert-Goton V, Yuan G, Battaglia A, Fredriksson S, Henkemeyer M. 60.  et al. 2013. Involvement of EphB1 receptors signalling in models of inflammatory and neuropathic pain. PLOS ONE 8:e53673 [Google Scholar]
  61. Leandro-Garcia LJ, Inglada-Pérez L, Pita G, Hjerpe E, Leskelä S. 61.  et al. 2013. Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy. J. Med. Genet. 50:599–605 [Google Scholar]
  62. Cruz-Orengo L, Figueroa JD, Velázquez I, Torrado A, Ortíz C. 62.  et al. 2006. Blocking EphA4 upregulation after spinal cord injury results in enhanced chronic pain. Exp. Neurol. 202:421–33 [Google Scholar]
  63. Kuijper S, Turner CJ, Adams RH. 63.  2007. Regulation of angiogenesis by Eph-ephrin interactions. Trends Cardiovasc. Med. 17:145–51 [Google Scholar]
  64. Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A. 64.  2007. A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev. Biol. 302:66–79 [Google Scholar]
  65. Frieden LA, Townsend TA, Vaught DB, Delaughter DM, Hwang Y. 65.  et al. 2010. Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev. Dyn. 239:3226–34 [Google Scholar]
  66. Salvucci O, Tosato G. 66.  2012. Essential roles of EphB receptors and EphrinB ligands in endothelial cell function and angiogenesis. Adv. Cancer Res. 114:21–57 [Google Scholar]
  67. Jellinghaus S, Poitz DM, Ende G, Augstein A, Weinert S. 67.  et al. 2013. Ephrin-A1/EphA4-mediated adhesion of monocytes to endothelial cells. Biochim. Biophys. Acta 1833:2201–11 [Google Scholar]
  68. Miao H, Wang B. 68.  2012. EphA receptor signaling—complexity and emerging themes. Semin. Cell Dev. Biol. 23:16–25 [Google Scholar]
  69. Wu Z, Luo H, Thorin E, Tremblay J, Peng J. 69.  et al. 2012. Possible role of Efnb1 protein, a ligand of Eph receptor tyrosine kinases, in modulating blood pressure. J. Biol. Chem. 287:15557–69 [Google Scholar]
  70. Brantley-Sieders DM, Chen J. 70.  2004. Eph receptor tyrosine kinases in angiogenesis: from development to disease. Angiogenesis 7:17–28 [Google Scholar]
  71. Biao-Xue R, Xi-Guang C, Shuan-Ying Y, Wei L, Zong-Juan M. 71.  2011. EphA2-dependent molecular targeting therapy for malignant tumors. Curr. Cancer Drug Targets 11:1082–97 [Google Scholar]
  72. Nakayama M, Nakayama A, van Lessen M, Yamamoto H, Hoffmann S. 72.  et al. 2013. Spatial regulation of VEGF receptor endocytosis in angiogenesis. Nat. Cell Biol. 15:249–60 [Google Scholar]
  73. Krasnoperov V, Kumar SR, Ley E, Li X, Scehnet J. 73.  et al. 2010. Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth. Am. J. Pathol. 176:2029–38 [Google Scholar]
  74. Li JL, Sainson RC, Oon CE, Turley H, Leek R. 74.  et al. 2011. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 71:6073–83 [Google Scholar]
  75. Goichberg P, Bai Y, D'Amario D, Ferreira-Martins J, Fiorini C. 75.  et al. 2011. The ephrin A1-EphA2 system promotes cardiac stem cell migration after infarction. Circ. Res. 108:1071–83 [Google Scholar]
  76. Goichberg P, Kannappan R, Cimini M, Bai Y, Sanada F. 76.  et al. 2013. Age-associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128:2211–23 [Google Scholar]
  77. Dries JL, Kent SD, Virag JA. 77.  2011. Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice. J. Physiol. 589:1725–40 [Google Scholar]
  78. Mansson-Broberg A, Siddiqui AJ, Genander M, Grinnemo KH, Hao X. 78.  et al. 2008. Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation. Biochem. Biophys. Res. Commun. 373:355–59 [Google Scholar]
  79. Ishii M, Mueller I, Nakajima T, Pasquale EB, Ogawa K. 79.  2011. EphB signaling inhibits gap junctional intercellular communication and synchronized contraction in cultured cardiomyocytes. Basic Res. Cardiol. 106:1057–68 [Google Scholar]
  80. Nishimura M, Jung EJ, Shah MY, Lu C, Spizzo R. 80.  et al. 2013. Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment. Cancer Discov. 3:1302–15 [Google Scholar]
  81. Lisabeth EM, Fernandez C, Pasquale EB. 81.  2012. Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms. Biochemistry 51:1464–75 [Google Scholar]
  82. Zhuang G, Song W, Amato K, Hwang Y, Lee K. 82.  et al. 2012. Effects of cancer-associated EPHA3 mutations on lung cancer. J. Natl. Cancer Inst. 104:1182–97 [Google Scholar]
  83. Udayakumar D, Zhang G, Ji Z, Njauw CN, Mroz P, Tsao H. 83.  2011. EphA2 is a critical oncogene in melanoma. Oncogene 30:4921–29 [Google Scholar]
  84. Lu M, Miller KD, Gokmen-Polar Y, Jeng M-H, Kinch MS. 84.  2003. EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity. Cancer Res. 63:3425–29 [Google Scholar]
  85. Gokmen-Polar Y, Toroni RA, Hocevar BA, Badve S, Zhao Q. 85.  et al. 2011. Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer. Breast Cancer Res. Treat. 127:375–84 [Google Scholar]
  86. Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L. 86.  et al. 2010. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res. 70:299–308 [Google Scholar]
  87. Ståhl S, Kaminskyy VO, Efazat G, Hyrslova Vaculova A, Rodriguez-Nieto S. 87.  et al. 2013. Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412. Cell Death Dis. 4:e454 [Google Scholar]
  88. Nakada M, Hayashi Y, Hamada J. 88.  2011. Role of Eph/ephrin tyrosine kinase in malignant glioma. Neuro Oncol. 13:1163–70 [Google Scholar]
  89. Day BW, Stringer BW, Al-Ejeh F, Ting MJ, Wilson J. 89.  et al. 2013. EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell 23:238–48 [Google Scholar]
  90. Miao H, Gale NW, Guo H, Qian J, Petty A. 90.  et al. 2014. EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties. Oncogene In press. doi: 10.1038/onc.2013.590
  91. Yang NY, Fernandez C, Richter M, Xiao Z, Valencia F. 91.  et al. 2011. Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells. Cell Signal. 23:201–12 [Google Scholar]
  92. Wang SD, Rath P, Lal B, Richard JP, Li Y. 92.  et al. 2012. EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 31:5132–43 [Google Scholar]
  93. Ying Z, Li Y, Wu J, Zhu X, Yang Y. 93.  et al. 2013. Loss of miR-204 expression enhances glioma migration and stem cell-like phenotype. Cancer Res. 73:990–99 [Google Scholar]
  94. Johnson RA, Wright KD, Poppleton H, Mohankumar KM, Finkelstein D. 94.  et al. 2010. Cross-species genomics matches driver mutations and cell compartments to model ependymoma. Nature 466:632–36 [Google Scholar]
  95. Li JJ, Xie D. 95.  2013. The roles and therapeutic potentials of Ephs and ephrins in lung cancer. Exp. Cell Res. 319:152–59 [Google Scholar]
  96. Saintigny P, Peng S, Zhang L, Sen B, Wistuba II. 96.  et al. 2012. Global evaluation of Eph receptors and ephrins in lung adenocarcinomas identifies EphA4 as an inhibitor of cell migration and invasion. Mol. Cancer Ther. 11:2021–32 [Google Scholar]
  97. Song W, Ma Y, Wang J, Brantley-Sieders D, Chen J. 97.  2014. JNK signaling mediates EPHA2-dependent tumor cell proliferation, motility, and cancer stem cell-like properties in non-small cell lung cancer. Cancer Res. 74:2444–54 [Google Scholar]
  98. Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR. 98.  et al. 2014. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J. Clin. Investig. 124:2037–49 [Google Scholar]
  99. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD. 99.  et al. 2008. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–75 [Google Scholar]
  100. Ji XD, Li G, Feng YX, Zhao JS, Li JJ. 100.  et al. 2011. EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res. 71:1156–66 [Google Scholar]
  101. Li G, Ji XD, Gao H, Zhao JS, Xu JF. 101.  et al. 2012. EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex. Nat. Commun. 3:667 [Google Scholar]
  102. Ferguson BD, Liu R, Rolle CE, Tan YH, Krasnoperov V. 102.  et al. 2013. The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target. PLOS ONE 8:e67668 [Google Scholar]
  103. Bulk E, Yu J, Hascher A, Koschmieder S, Wiewrodt R. 103.  et al. 2012. Mutations of the EPHB6 receptor tyrosine kinase induce a pro-metastatic phenotype in non-small cell lung cancer. PLOS ONE 7:e44591 [Google Scholar]
  104. Thanapprapasr D, Hu W, Sood AK, Coleman RL. 104.  2012. Moving beyond VEGF for anti-angiogenesis strategies in gynecologic cancer. Curr. Pharm. Des. 18:2713–19 [Google Scholar]
  105. Héroult M, Schaffner F, Pfaff D, Prahst C, Kirmse R. 105.  et al. 2010. EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell–expressed ephrinB2. Mol. Cancer Res. 8:1297–309 [Google Scholar]
  106. Xu K, Broder CC, Nikolov DB. 106.  2012. Ephrin-B2 and ephrin-B3 as functional henipavirus receptors. Semin. Cell Dev. Biol. 23:116–23 [Google Scholar]
  107. Dewannieux M, Vernochet C, Ribet D, Bartosch B, Cosset FL, Heidmann T. 107.  2011. The mouse IAPE endogenous retrovirus can infect cells through any of the five GPI-anchored Ephrin A proteins. PLOS Pathog. 7:e1002309 [Google Scholar]
  108. Chakraborty S, Veettil MV, Bottero V, Chandran B. 108.  2012. Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc. Natl. Acad. Sci. USA 109:E1163–72 [Google Scholar]
  109. Hahn AS, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J. 109.  et al. 2012. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus. Nat. Med. 18:961–66 [Google Scholar]
  110. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I. 110.  et al. 2011. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 17:589–95 [Google Scholar]
  111. Chen W, Sin SH, Wen KW, Damania B, Dittmer DP. 111.  2012. Hsp90 inhibitors are efficacious against Kaposi sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins. PLOS Pathog. 8:e1003048 [Google Scholar]
  112. Karlas A, Machuy N, Shin Y, Pleissner KP, Artarini A. 112.  et al. 2010. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463:818–22 [Google Scholar]
  113. Genander M, Frisen J. 113.  2010. Ephrins and Eph receptors in stem cells and cancer. Curr. Opin. Cell Biol. 22:611–16 [Google Scholar]
  114. Matsuo K, Otaki N. 114.  2012. Bone cell interactions through Eph/ephrin: bone modeling, remodeling and associated diseases. Cell Adhes. Migr. 6:148–56 [Google Scholar]
  115. Lin S, Wang B, Getsios S. 115.  2012. Eph/ephrin signaling in epidermal differentiation and disease. Semin. Cell Dev. Biol. 23:92–101 [Google Scholar]
  116. Gordon K, Kochkodan JJ, Blatt H, Lin SY, Kaplan N. 116.  et al. 2013. Alteration of the EphA2/ephrin-A signaling axis in psoriatic epidermis. J. Investig. Dermatol. 133:712–22 [Google Scholar]
  117. Genander M, Holmberg J, Frisen J. 117.  2010. Ephrins negatively regulate cell proliferation in the epidermis and hair follicle. Stem Cells 28:1196–205 [Google Scholar]
  118. Szepietowska B, Zhu W, Czyzyk J, Eid T, Sherwin RS. 118.  2013. EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia. Diabetes 62:1282–88 [Google Scholar]
  119. Jain R, Jain D, Liu Q, Bartosinska B, Wang J. 119.  et al. 2013. Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets. Diabetologia 56:1350–55 [Google Scholar]
  120. Zhang R, Zhong NN, Liu XG, Yan H, Qiu C. 120.  et al. 2010. Is the EFNB2 locus associated with schizophrenia? Single nucleotide polymorphisms and haplotypes analysis. Psychiatry Res. 180:5–9 [Google Scholar]
  121. Shi S, Liu J, Joshi SB, Krasnoperov V, Gill P. 121.  et al. 2012. Biophysical characterization and stabilization of the recombinant albumin fusion protein sEphB4-HSA. J. Pharm. Sci. 101:1969–84 [Google Scholar]
  122. Djokovic D, Trindade A, Gigante J, Badenes M, Silva L. 122.  et al. 2010. Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer 10:641 [Google Scholar]
  123. Brar M, Cheng L, Yuson R, Mojana F, Freeman WR, Gill PS. 123.  2010. Ocular safety profile and intraocular pharmacokinetics of an antagonist of EphB4/EphrinB2 signalling. Br. J. Ophthalmol. 94:1668–73 [Google Scholar]
  124. Scehnet JS, Ley EJ, Krasnoperov V, Liu R, Manchanda PK. 124.  et al. 2009. The role of Ephs, Ephrins, and growth factors in Kaposi sarcoma and implications of EphrinB2 blockade. Blood 113:254–63 [Google Scholar]
  125. Oricchio E, Nanjangud G, Wolfe AL, Schatz JH, Mavrakis KJ. 125.  et al. 2011. The eph-receptor a7 is a soluble tumor suppressor for follicular lymphoma. Cell 147:554–64 [Google Scholar]
  126. Zisch AH, Zeisberger SM, Ehrbar M, Djonov V, Weber CC. 126.  et al. 2004. Engineered fibrin matrices for functional display of cell membrane-bound growth factor-like activities: study of angiogenic signaling by ephrin-B2. Biomaterials 25:3245–57 [Google Scholar]
  127. Saik JE, Gould DJ, Keswani AH, Dickinson ME, West JL. 127.  2011. Biomimetic hydrogels with immobilized ephrinA1 for therapeutic angiogenesis. Biomacromolecules 12:2715–22 [Google Scholar]
  128. Lee HY, Mohammed KA, Peruvemba S, Goldberg EP, Nasreen N. 128.  2011. Targeted lung cancer therapy using ephrinA1-loaded albumin microspheres. J. Pharm. Pharmacol. 63:1401–10 [Google Scholar]
  129. Lohmuller T, Triffo S, O'Donoghue GP, Xu Q, Coyle MP, Groves JT. 129.  2011. Supported membranes embedded with fixed arrays of gold nanoparticles. Nano Lett. 11:4912–18 [Google Scholar]
  130. Shaw A, Lundin V, Petrova E, Fördōs F, Benson E. 130.  et al. 2014. Spatial control of membrane receptor function using ligand nanocalipers. Nat. Methods 11:841–46 [Google Scholar]
  131. Kiewlich D, Zhang J, Gross C, Xia W, Larsen B. 131.  et al. 2006. Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do not inhibit tumor growth. Neoplasia 8:18–30 [Google Scholar]
  132. Coffman KT, Hu M, Carles-Kinch K, Tice D, Donacki N. 132.  et al. 2003. Differential EphA2 epitope display on normal versus malignant cells. Cancer Res. 63:7907–12 [Google Scholar]
  133. Merritt WM, Kamat AA, Hwang JY, Bottsford-Miller J, Lu C. 133.  et al. 2010. Clinical and biological impact of EphA2 overexpression and angiogenesis in endometrial cancer. Cancer Biol. Ther. 10:1306–14 [Google Scholar]
  134. Bruckheimer EM, Fazenbaker CA, Gallagher S, Mulgrew K, Fuhrmann S. 134.  et al. 2009. Antibody-dependent cell-mediated cytotoxicity effector-enhanced EphA2 agonist monoclonal antibody demonstrates potent activity against human tumors. Neoplasia 11:509–17 [Google Scholar]
  135. Lee JW, Stone RL, Lee SJ, Nam EJ, Roh JW. 135.  et al. 2010. EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin. Cancer Res. 16:2562–70 [Google Scholar]
  136. Abéngozar MA, de Frutos S, Ferreiro S, Soriano J, Perez-Martinez M. 136.  et al. 2012. Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119:4565–76 [Google Scholar]
  137. Spannuth WA, Mangala LS, Stone RL, Carroll AR, Nishimura M. 137.  et al. 2010. Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma. Mol. Cancer Ther. 9:2377–88 [Google Scholar]
  138. Lamberto I, Qin H, Noberini R, Premkumar L, Bourgin C. 138.  et al. 2012. Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor. Biochem. J. 445:47–56 [Google Scholar]
  139. Koolpe M, Burgess R, Dail M, Pasquale EB. 139.  2005. EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity. J. Biol. Chem. 280:17301–11 [Google Scholar]
  140. Duggineni S, Mitra S, Lamberto I, Han X, Xu Y. 140.  et al. 2013. Design and synthesis of potent bivalent peptide agonists targeting the EphA2 receptor. ACS Med. Chem. Lett. 4:344–48 [Google Scholar]
  141. Noberini R, Mitra S, Salvucci O, Valencia F, Duggineni S. 141.  et al. 2011. PEGylation potentiates the effectiveness of an antagonistic peptide that targets the EphB4 receptor with nanomolar affinity. PLOS ONE 6:e28611 [Google Scholar]
  142. Zhang R, Xiong C, Huang M, Zhou M, Huang Q. 142.  et al. 2011. Peptide-conjugated polymeric micellar nanoparticles for Dual SPECT and optical imaging of EphB4 receptors in prostate cancer xenografts. Biomaterials 32:5872–79 [Google Scholar]
  143. Wang S, Noberini R, Stebbins JL, Das S, Zhang Z. 143.  et al. 2013. Targeted delivery of paclitaxel to EphA2-expressing cancer cells. Clin. Cancer Res. 19:128–37 [Google Scholar]
  144. Mitra S, Duggineni S, Koolpe M, Zhu X, Huang Z, Pasquale EB. 144.  2010. Structure-activity relationship analysis of peptides targeting the EphA2 receptor. Biochemistry 49:6687–95 [Google Scholar]
  145. Wang S, Placzek WJ, Stebbins JL, Mitra S, Noberini R. 145.  et al. 2012. Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J. Med. Chem. 55:2427–36 [Google Scholar]
  146. Duggineni S, Mitra S, Noberini R, Han X, Lin N. 146.  et al. 2013. Design, synthesis and characterization of novel small molecular inhibitors of ephrin-B2 binding to EphB4. Biochem. Pharmacol. 85:507–13 [Google Scholar]
  147. Wu B, Zhang Z, Noberini R, Barile E, Giulianotti M. 147.  et al. 2013. HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery. Chem. Biol. 20:19–33 [Google Scholar]
  148. Incerti M, Tognolini M, Russo S, Pala D, Giorgio C. 148.  et al. 2013. Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J. Med. Chem. 56:2936–47 [Google Scholar]
  149. Huang J, Hu W, Bottsford-Miller J, Liu T, Han HD. 149.  et al. 2014. Crosstalk between EphA2 and BRaf/CRaf is a key determinant of response to dasatinib. Clin. Cancer Res. 20:1846–55 [Google Scholar]
  150. Martiny-Baron G, Holzer P, Billy E, Schnell C, Brueggen J. 150.  et al. 2010. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis 13:259–67 [Google Scholar]
  151. Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML. 151.  et al. 2010. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465:483–86 [Google Scholar]
  152. Shen H, Rodriguez-Aguayo C, Xu R, Gonzalez-Villasana V, Mai J. 152.  et al. 2013. Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery. Clin. Cancer Res. 19:1806–15 [Google Scholar]
  153. Shahzad MM, Lu C, Lee JW, Stone RL, Mitra R. 153.  et al. 2009. Dual targeting of EphA2 and FAK in ovarian carcinoma. Cancer Biol. Ther. 8:1027–34 [Google Scholar]
  154. Jackson D, Gooya J, Mao S, Kinneer K, Xu L. 154.  et al. 2008. A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res. 68:9367–74 [Google Scholar]
  155. Lee JW, Han HD, Shahzad MM, Kim SW, Mangala LS. 155.  et al. 2009. EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma. J. Natl. Cancer Inst. 101:1193–205 [Google Scholar]
  156. Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB. 156.  et al. 2007. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur. J. Nucl. Med. Mol. Imaging 34:2024–36 [Google Scholar]
  157. Wang JL, Liu YL, Li Y, Dai WB, Guo ZM. 157.  et al. 2012. EphA2 targeted doxorubicin stealth liposomes as a therapy system for choroidal neovascularization in rats. Investig. Ophthalmol. Vis. Sci. 53:7348–57 [Google Scholar]
  158. Dickerson EB, Blackburn WH, Smith MH, Kapa LB, Lyon LA, McDonald JF. 158.  2010. Chemosensitization of cancer cells by siRNA using targeted nanogel delivery. BMC Cancer 10:10 [Google Scholar]
  159. Vearing C, Lee FT, Wimmer-Kleikamp S, Spirkoska V, To C. 159.  et al. 2005. Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents. Cancer Res. 65:6745–54 [Google Scholar]
  160. Gobin AM, Moon JJ, West JL. 160.  2008. EphrinA1-targeted nanoshells for photothermal ablation of prostate cancer cells. Int. J. Nanomedicine 3:351–58 [Google Scholar]
  161. Mao W, Luis E, Ross S, Silva J, Tan C. 161.  et al. 2004. EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer. Cancer Res. 64:781–88 [Google Scholar]
  162. Li D, Liu S, Liu R, Zhou Y, Park R. 162.  et al. 2013. EphB4-targeted imaging with antibody h131, h131-F(ab′)2 and h131-Fab. Mol. Pharm. 10:4527–33 [Google Scholar]
  163. Liu S, Li D, Park R, Liu R, Xia Z. 163.  et al. 2013. PET imaging of colorectal and breast cancer by targeting EphB4 receptor with 64Cu-labeled hAb47 and hAb131 antibodies. J. Nucl. Med. 54:1094–100 [Google Scholar]
  164. You J, Zhang R, Xiong C, Zhong M, Melancon M. 164.  et al. 2012. Effective photothermal chemotherapy using doxorubicin-loaded gold nanospheres that target EphB4 receptors in tumors. Cancer Res. 72:4777–86 [Google Scholar]
  165. Huang M, Xiong C, Lu W, Zhang R, Zhou M. 165.  et al. 2014. Dual-modality micro-positron emission tomography/computed tomography and near-infrared fluorescence imaging of EphB4 in orthotopic glioblastoma xenograft models. Mol. Imaging Biol. 16:74–84 [Google Scholar]
  166. You J, Wang Z, Du Y, Yuan H, Zhang P. 166.  et al. 2013. Specific tumor delivery of paclitaxel using glycolipid-like polymer micelles containing gold nanospheres. Biomaterials 34:4510–19 [Google Scholar]
  167. Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR. 167.  et al. 2013. T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol. Ther. 21:629–37 [Google Scholar]
  168. Hammond SA, Lutterbuese R, Roff S, Lutterbuese P, Schlereth B. 168.  et al. 2007. Selective targeting and potent control of tumor growth using an EphA2/CD3-bispecific single-chain antibody construct. Cancer Res. 67:3927–35 [Google Scholar]
  169. Annunziata CM, Kohn EC, LoRusso P, Houston ND, Coleman RL. 169.  et al. 2013. Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Investig. New Drugs 31:77–84 [Google Scholar]
  170. Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A. 170.  et al. 2014. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene 33:2179–90 [Google Scholar]
  171. Dong Y, Harrington BS, Adams MN, Wortmann A, Stephenson SA. 171.  et al. 2014. Activation of membrane-bound proteins and receptor systems: a link between tissue kallikrein and the KLK-related peptidases. Biol. Chem. 395:977–90 [Google Scholar]
  172. Ji YJ, Hwang YS, Mood K, Cho HJ, Lee HS. 172.  et al. 2014. EphrinB2 affects apical constriction in Xenopus embryos and is regulated by ADAM10 and flotillin-1. Nat. Commun. 5:3516 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-011112-140226
Loading
/content/journals/10.1146/annurev-pharmtox-011112-140226
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error