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Eph Receptor Tyrosine Kinases in Angiogenesis: From Development to Disease

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Abstract

Angiogenesis, the process by which new blood vessels sprout and branch from existing vasculature, is crucial for vascular remodeling during embryogenesis and in normal tissue homeostasis, such as in the female reproductive tract. Angiogenesis can also contribute to the pathogenesis of diseases such as cancer and retinopathy. The Eph family of receptor tyrosine kinases and their ligands, called ephrins, has emerged as critical regulators of vascular remodeling in the embryo. More recently, these molecules have been associated with post-natal angiogenic remodeling and tumor neovascularization. This review provides an overview of recent advances in our understanding of Eph/ephrins in angiogenesis, with an emphasis on development and disease, and the potential for targeting these molecules in anti-angiogenic therapy.

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References

  1. Griffioen AW, Molema G. Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 2000; 52 (2): 237–68.

    Google Scholar 

  2. Yancopoulos GD, Davis S, Gale NW et al. Vascular-specific growth factors and blood vessel formation. Nature 2000; 407 (6801): 242–8.

    Google Scholar 

  3. Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee. Cell 1997; 90 (3): 403–4.

    Google Scholar 

  4. Sasaki E, Hikono H, Kaku Y et al. EphA9, a novel avian receptor tyrosine kinase gene. Gene 2003; 316 (Oct 16): 103–10.

    Google Scholar 

  5. Menzel P, Valencia F, Godement P et al. Ephrin-A6, a new ligand for EphA receptors in the developing visual system. Dev Biol 2001; 230 (1): 74–88.

    Google Scholar 

  6. Gale NW, Holland SJ, Valenzuela DM et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 1996; 17 (1): 9–19.

    Google Scholar 

  7. Cheng N, Brantley DM, Chen J. The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 2002; 13 (1): 75–85.

    Google Scholar 

  8. Murai KK, Pasquale EB. 'Eph'ective signaling: Forward, reverse and crosstalk. J Cell Sci 2003; 116 (Pt 14): 2823–32.

    Google Scholar 

  9. Bruckner K, Pasquale EB, Klein R. Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 1997; 275 (5306): 1640–3.

    Google Scholar 

  10. Holland SJ, Gale NW, Mbamalu G et al. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 1996; 383 (6602): 722–5.

    Google Scholar 

  11. Palmer A, Zimmer M, Erdmann KS et al. EphrinB phosphorylation and reverse signaling: Regulation by Src kinases and PTPBL phosphatase. Mol Cell 2002; 9 (4): 725–37.

    Google Scholar 

  12. Marston DJ, Dickinson S, Nobes CD. Rac-dependent transendocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol 2003; 5 (10): 879–88.

    Google Scholar 

  13. Zimmer M, Palmer A, Kohler J et al. EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 2003; 5 (10): 869–78.

    Google Scholar 

  14. Davy A, Gale NW, Murray EW et al. Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev 1999; 13 (23): 3125–35.

    Google Scholar 

  15. Davy A, Robbins SM. Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner. EMBO J 2000; 19 (20): 5396–405.

    Google Scholar 

  16. Huai J, Drescher U. An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein. J Biol Chem 2001; 276 (9): 6689–94.

    Google Scholar 

  17. Holder N, Klein R. Eph receptors and ephrins: effectors of morphogenesis. Development 1999; 126 (10): 2033–44.

    Google Scholar 

  18. Dodelet VC, Pasquale EB. Eph receptors and ephrin ligands: Embryogenesis to tumorigenesis. Oncogene 2000; 19 (49): 5614–9.

    Google Scholar 

  19. Coulthard MG, Duffy S, Down M et al. The role of the Ephephrin signalling system in the regulation of developmental patterning. Int J Dev Biol 2002; 46 (4): 375–84.

    Google Scholar 

  20. Dottori M, Hartley L, Galea M et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci USA 1998; 95 (22): 13248–53.

    Google Scholar 

  21. Coonan JR, Greferath U, Messenger J et al. Development and reorganization of corticospinal projections in EphA4 deficient mice. J Comp Neurol 2001; 436 (2): 248–62.

    Google Scholar 

  22. Kullander K, Croll SD, Zimmer M et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev 2001; 15 (7): 877–88.

    Google Scholar 

  23. Kullander K, Mather NK, Diella F et al. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 2001; 29 (1): 73–84.

    Google Scholar 

  24. Martone ME, Holash JA, Bayardo A et al. Immunolocalization of the receptor tyrosine kinase EphA4 in the adult rat central nervous system. Brain Res 1997; 771 (2): 238–50.

    Google Scholar 

  25. Ethell IM, Irie F, Kalo MS et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 2001; 31 (6): 1001–13.

    Google Scholar 

  26. Irie F, Yamaguchi Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nat Neurosci 2002; 5 (11): 1117–8.

    Google Scholar 

  27. Holmberg J, Frisen J. Ephrins are not only unattractive. Trends Neurosci 2002; 25 (5): 239–43.

    Google Scholar 

  28. Drescher U. The Eph family in the patterning of neural development. Curr Biol 1997; 7 (12): R799–807.

    Google Scholar 

  29. Wilkinson DG. Eph receptors and ephrins: Regulators of guidance and assembly. Int Rev Cytol 2000; 196: 177–244.

    Google Scholar 

  30. Tepass U, Godt D, Winklbauer R. Cell sorting in animal development: signalling and adhesive mechanisms in the formation of tissue boundaries. Curr Opin Genet Dev 2002; 12 (5): 572–82.

    Google Scholar 

  31. Risau W, Flamme I. Vasculogenesis. Annu Rev Cell Dev Biol 1995; 11: 73–91.

    Google Scholar 

  32. Patan S. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J Neurooncol 2000; 50 (1–2): 1–15.

    Google Scholar 

  33. Folkman J, D'Amore PA. Blood vessel formation: What is its molecular basis? Cell 1996; 87 (7): 1153–5.

    Google Scholar 

  34. Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins Eph receptors in angiogenesis 25 revealed by ephrin-B2 and its receptor Eph-B4. Cell 1998; 93 (5): 741–53.

    Google Scholar 

  35. Adams RH, Wilkinson GA, Weiss C et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: Demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 1999; 13 (3): 295–306.

    Google Scholar 

  36. Helbling PM, Saulnier DM, Brandli AW. The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 2000; 127 (2): 269–78.

    Google Scholar 

  37. Othman-Hassan K, Patel K, Papoutsi M et al. Arterial identity of endothelial cells is controlled by local cues. Dev Biol 2001; 237 (2): 398–409.

    Google Scholar 

  38. Baker RK, Antin PB. Ephs and ephrins during early stages of chick embryogenesis. Dev Dyn 2003; 228 (1): 128–42.

    Google Scholar 

  39. Gerety SS, Wang HU, Chen ZF et al. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 1999; 4 (3): 403–14.

    Google Scholar 

  40. Adams RH, Diella F, Hennig S et al. The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 2001; 104 (1): 57–69.

    Google Scholar 

  41. Wang Z, Cohen K, Shao Y et al. Ephrin receptor, EphB4, regulates ES cell differentiation of primitive mammalian hemangioblasts, blood, cardiomyocytes, and blood vessels. Blood 2003; 4: 4.

    Google Scholar 

  42. Gale NW, Baluk P, Pan L et al. Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth-muscle cells. Dev Biol 2001; 230 (2): 151–60.

    Google Scholar 

  43. Shin D, Garcia-Cardena G, Hayashi S et al. Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev Biol 2001; 230 (2): 139–50.

    Google Scholar 

  44. Oike Y, Ito Y, Hamada K et al. Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells. Blood 2002; 100 (4): 1326–33.

    Google Scholar 

  45. Gerety SS, Anderson DJ. Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 2002; 129 (6): 1397–410.

    Google Scholar 

  46. Zhang XQ, Takakura N, Oike Y et al. Stromal cells expressing ephrin-B2 promote the growth and sprouting of ephrin-B2 (+) endothelial cells. Blood 2001; 98 (4): 1028–37.

    Google Scholar 

  47. Fuller T, Korff T, Kilian A et al. Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells. J Cell Sci 2003; 116 (Pt 12): 2461–70.

    Google Scholar 

  48. Hamada K, Oike Y, Ito Y et al. Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 2003; 23 (2): 190–7.

    Google Scholar 

  49. Sullivan DC, Bicknell R. New molecular pathways in angiogenesis. Br J Cancer 2003; 89(2): 228–31.

    Google Scholar 

  50. Goumans MJ, Lebrin F, Valdimarsdottir G. Controlling the angiogenic switch: A balance between two distinct TGF-b receptor signaling pathways. Trends Cardiovasc Med 2003; 13 (7): 301–7.

    Google Scholar 

  51. Lawson ND, Scheer N, Pham VN et al. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 2001; 128 (19): 3675–83.

    Google Scholar 

  52. Zhong TP, Childs S, Leu JP et al. Gridlock signalling pathway fashions the first embryonic artery. Nature 2001; 414 (6860): 216–20.

    Google Scholar 

  53. Lawson ND, Vogel AM, Weinstein BM. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 2002; 3 (1): 127–36.

    Google Scholar 

  54. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet 2000; 26 (3): 328–31.

    Google Scholar 

  55. Ota T, Fujii M, Sugizaki T et al. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol 2002; 193 (3): 299–318.

    Google Scholar 

  56. Deschamps J, van den Akker E, Forlani S et al. Initiation, establishment and maintenance of Hox gene expression patterns in the mouse. Int J Dev Biol 1999; 43 (7 Spec No): 635–50.

    Google Scholar 

  57. Veraksa A, Del Campo M, McGinnis W. Developmental patterning genes and their conserved functions: From model organisms to humans. Mol Genet Metab 2000; 69 (2): 85–100.

    Google Scholar 

  58. Kmita M, Duboule D. Organizing axes in time and space; 25 years of colinear tinkering. Science 2003; 301 (5631): 331–3.

    Google Scholar 

  59. Stadler HS, Higgins KM, Capecchi MR. Loss of Eph-receptor expression correlates with loss of cell adhesion and chondrogenic capacity in Hoxa13 mutant limbs. Development 2001; 128 (21): 4177–88.

    Google Scholar 

  60. Morgan EA, Nguyen SB, Scott V et al. Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia. Development 2003; 130 (14): 3095–109.

    Google Scholar 

  61. Takahashi H, Ikeda T. Molecular cloning and expression of rat and mouse B61 gene: Implications on organogenesis. Oncogene 1995; 11 (5): 879–83.

    Google Scholar 

  62. McBride JL, Ruiz JC. Ephrin-A1 is expressed at sites of vascular development in the mouse. Mech Dev 1998;77 (2): 201–4.

    Google Scholar 

  63. Pandey A, Shao H, Marks RM et al. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis. Science 1995; 268 (5210): 567–9.

    Google Scholar 

  64. Daniel TO, Stein E, Cerretti DP et al. ELK and LERK-2 in developing kidney and microvascular endothelial assembly. Kidney Int Suppl 1996; 57: S73–81.

    Google Scholar 

  65. Ogawa K, Pasqualini R, Lindberg RA et al. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 2000; 19 (52): 6043–52.

    Google Scholar 

  66. Cheng N, Chen J. Tumor necrosis factor-alpha induction of endothelial ephrin A1 expression is mediated by a p38 MAPKand SAPK/JNK-dependent but nuclear factor-kappa B-independent mechanism. J Biol Chem 2001; 276 (17): 13771–7.

    Google Scholar 

  67. Brantley DM, Cheng N, Thompson EJ et al. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 2002; 21 (46): 7011–26.

    Google Scholar 

  68. Myers C, Charboneau A, Boudreau N. Homeobox B3 promotes capillary morphogenesis and angiogenesis. J Cell Biol 2000; 148 (2): 343–51.

    Google Scholar 

  69. Cheng N, Brantley DM, Liu H et al. Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis. Mol Cancer Res 2002; 1 (1): 2–11.

    Google Scholar 

  70. Stein E, Lane AA, Cerretti DP et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 1998; 12 (5): 667–78.

    Google Scholar 

  71. Nagashima K, Endo A, Ogita H et al. Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Mol Biol Cell 2002; 13 (12): 4231–42.

    Google Scholar 

  72. Sawai Y, Tamura S, Fukui K et al. Expression of ephrin-B1 in hepatocellular carcinoma: Possible involvement in neovascularization. J Hepatol 2003; 39 (6):991–6.

    Google Scholar 

  73. Huynh-Do U, Vindis C, Liu H et al. Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis. J Cell Sci 2002; 115 (Pt 15): 3073–81.

    Google Scholar 

  74. Li J, Zhang YP, Kirsner RS. Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix. Microsc Res Tech 2003; 60 (1): 107–14.

    Google Scholar 

  75. Semenza GL. Angiogenesis in ischemic and neoplastic disorders. Annu Rev Med 2003; 54: 17–28.

    Google Scholar 

  76. Davis JS, Rueda BR, Spanel-Borowski K. Microvascular endothelial cells of the corpus luteum. Reprod Biol Endocrinol 2003; 1 (1): 89.

    Google Scholar 

  77. Smith SK. Regulation of angiogenesis in the endometrium. Trends Endocrinol Metab 2001; 12 (4): 147–51.

    Google Scholar 

  78. Wulff C, Weigand M, Kreienberg R et al. Angiogenesis during primate placentation in health and disease. Reproduction 2003; 126 (5): 569–77.

    Google Scholar 

  79. Vindis C, Cerretti DP, Daniel TO et al. EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol 2003; 162 (4): 661–71.

    Google Scholar 

  80. Maekawa H, Oike Y, Kanda S et al. Ephrin-b2 induces migration of endothelial cells through the phosphatidylinositol-3 kinase pathway and promotes angiogenesis in adult vasculature. Arterioscler Thromb Vasc Biol 2003; 23 (11): 2008–14.

    Google Scholar 

  81. Brantley-Sieders DM, Caughron J, Hicks D et al. EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 2004 (in press).

  82. Rees MC, Bicknell R. Angiogenesis in the endometrium. Angiogenesis 1998; 2 (1): 29–35.

    Google Scholar 

  83. Hull ML, Charnock-Jones DS, Chan CL et al. Antiangiogenic agents are effective inhibitors of endometriosis. J Clin Endocrinol Metab 2003; 88 (6): 2889–99.

    Google Scholar 

  84. Fujiwara H, Yoshioka S, Tatsumi K et al. Human endometrial epithelial cells express ephrin A1: Possible interaction between human blastocysts and endometrium via Eph-ephrin system. J Clin Endocrinol Metab 2002; 87 (12): 5801–7.

    Google Scholar 

  85. Kao LC, Germeyer A, Tulac S et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003; 144 (7): 2870–81.

    Google Scholar 

  86. Berclaz G, Karamitopoulou E, Mazzucchelli L et al. Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma. Ann Oncol 2003; 14 (2): 220–6.

    Google Scholar 

  87. Takai N, Miyazaki T, Fujisawa K et al. Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep 2001; 8 (3): 567–73.

    Google Scholar 

  88. Ozuysal S, Bilgin T, Ozan H et al. Angiogenesis in endometrial carcinoma: correlation with survival and clinicopathologic risk factors. Gynecol Obstet Invest 2003; 55 (3): 173–7.

    Google Scholar 

  89. Egawa M, Yoshioka S, Higuchi T et al. Ephrin B1 is expressed on human luteinizing granulosa cells in corpora lutea of the early luteal phase: the possible involvement of the B class Eph-ephrin system during corpus luteum formation. J Clin Endocrinol Metab 2003; 88 (9):4384–92.

    Google Scholar 

  90. Schaner ME, Ross DT, Ciaravino G et al. Gene expression patterns in ovarian carcinomas. Mol Biol Cell 2003; 14 (11): 4376–86.

    Google Scholar 

  91. Adamis AP, Aiello LP, D'Amato RA. Angiogenesis and ophthalmic disease. Angiogenesis 1999; 3 (1): 9–14.

    Google Scholar 

  92. Steinle JJ, Meininger CJ, Chowdhury U et al. Role of ephrin B2 in human retinal endothelial cell proliferation and migration. Cell Signal 2003; 15 (11): 1011–7.

    Google Scholar 

  93. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002; 29 (6 Suppl 16): 15–8.

    Google Scholar 

  94. Ribatti D, Vacca A, Dammacco F. New non-angiogenesis dependent pathways for tumour growth. Eur J Cancer 2003; 39 (13): 1835–41.

    Google Scholar 

  95. Asahara T, Masuda H, Takahashi T et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85 (3): 221–8.

    Google Scholar 

  96. de Bont ES, Guikema JE, Scherpen F et al. Mobilized human CD34+ hematopoietic stem cells enhance tumor growth in a nonobese diabetic/severe combined immunodeficient mouse model of human non-Hodgkin's lymphoma. Cancer Res 2001; 61 (20): 7654–9.

    Google Scholar 

  97. Shirakawa K, Furuhata S, Watanabe I et al. Induction of vasculogenesis in breast cancer models. Br J Cancer 2002; 87 (12): 1454–61.

    Google Scholar 

  98. Bolontrade MF, Zhou RR, Kleinerman ES. Vasculogenesis Plays a Role in the Growth of Ewing's Sarcoma in vivo. Clin Cancer Res 2002; 8 (11): 3622–7.

    Google Scholar 

  99. Muta M, Matsumoto G, Hiruma K et al. Impact of vasculogenesis on solid tumor growth in a rat model. Oncol Rep 2003; 10 (5): 1213–8.

    Google Scholar 

  100. Vajkoczy P, Blum S, Lamparter M et al. Multistep nature of microvascular recruitment of ex vivo-expanded embryonic endothelial progenitor cells during tumor angiogenesis. J Exp Med 2003; 197 (12): 1755–65.

    Google Scholar 

  101. Chen CT, Moffat DH, Enming JS et al. Delivery of soluble EphB4 receptor gene as an antiangiogenic strategy for cancer treatment. (Keystone Symposium) Angiogenesis in Cancer and Other Diseases: From Gene to Function to Therapy 2002: 149.

  102. Easty DJ, Herlyn M, Bennett DC. Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer 1995; 60 (1): 129–36.

    Google Scholar 

  103. Hess AR, Seftor EA, Gardner LM et al. Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: Role of epithelial cell kinase (Eck/EphA2). Cancer Res 2001; 61 (8): 3250–5.

    Google Scholar 

  104. Straume O, Akslen LA. Importance of vascular phenotype by basic fibroblast growth factor, and influence of the angiogenic factors basic fibroblast growth factor/fibroblast growth factor receptor-1 and ephrin-A1/EphA2 on melanoma progression. Am J Pathol 2002; 160 (3): 1009–19.

    Google Scholar 

  105. Walker-Daniels J, Coffman K, Azimi M et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate 1999; 41 (4): 275–80.

    Google Scholar 

  106. Zeng G, Hu Z, Kinch MS et al. High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol 2003; 163 (6): 2271–6.

    Google Scholar 

  107. Zelinski DP, Zantek ND, Stewart JC et al. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 2001; 61 (5): 2301–6.

    Google Scholar 

  108. Cheng N, Brantley D, Fang WB et al. Inhibition of VEGFdependent multistage carcinogenesis by soluble EphA receptors. Neoplasia 2003; 5 (5): 445–56.

    Google Scholar 

  109. Dobrzanski P, Hunter K, Jones-Bolin S et al. Antiangiogenic and Antitumor Efficacy of EphA2 Receptor Antagonist. Cancer Res 2004; 64 (3): 910–9.

    Google Scholar 

  110. Ruiz JC, Robertson EJ. The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development. Mech Dev 1994; 46 (2):87–100.

    Google Scholar 

  111. Bergers G, Brekken R, McMahon G et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2 (10): 737–44.

    Google Scholar 

  112. Prewett M, Huber J, Li Y et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 1999; 59 (20): 5209–18.

    Google Scholar 

  113. Deroanne C, Vouret-Craviari V, Wang B et al. EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J Cell Sci 2003; 116 (Pt 7): 1367–76.

    Google Scholar 

  114. Ogita H, Kunimoto S, Kamioka Y et al. EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. Circ Res 2003; 93 (1): 23–31.

    Google Scholar 

  115. Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J 2001; 7 (5): 427–36.

    Google Scholar 

  116. Gasparini G. Metronomic scheduling: The future of chemotherapy? Lancet Oncol 2001; 2 (12): 733–40.

    Google Scholar 

  117. Hahnfeldt P, Folkman J, Hlatky L. Minimizing long-term tumor burden: The logic for metronomic chemotherapeutic dosing and its antiangiogenic basis. J Theor Biol 2003; 220 (4): 545–54.

    Google Scholar 

  118. Lu M, Miller KD, Gokmen-Polar Y et al. EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity. Cancer Res 2003; 63 (12): 3425–9.

    Google Scholar 

  119. Nikolova Z, Djonov V, Zuercher G et al. Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase Eph receptors in angiogenesis 27 EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis. J Cell Sci 1998; 111 (Pt 18): 2741–51.

    Google Scholar 

  120. Munarini N, Jager R, Abderhalden 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 (Pt 1): 25–37.

    Google Scholar 

  121. Vaidya A, Pniak A, Lemke G et al. EphA3 null mutants do not demonstrate motor axon guidance defects. Mol Cell Biol 2003; 23 (22): 8092–8.

    Google Scholar 

  122. Leighton PA, Mitchell KJ, Goodrich LV et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 2001; 410 (6825): 174–9.

    Google Scholar 

  123. Schmidt C, Christ B, Maden M et al. Regulation of Epha4 expression in paraxial and lateral plate mesoderm by ectodermderived signals. Dev Dyn 2001; 220 (4): 377–86.

    Google Scholar 

  124. Karam SD, Dottori M, Ogawa K et al. EphA4 is not required for Purkinje cell compartmentation. Brain Res Dev Brain Res 2002; 135 (1–2): 29–38.

    Google Scholar 

  125. Murai KK, Nguyen LN, Irie F et al. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci 2003; 6 (2): 153–60.

    Google Scholar 

  126. Holzman LB, Marks RM, Dixit VM. A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Mol Cell Biol 1990; 10 (11): 5830–8.

    Google Scholar 

  127. Beckmann MP, Cerretti DP, Baum P et al. Molecular characterization of a family of ligands for eph-related tyrosine kinase receptors. EMBO J 1994; 13 (16): 3757–62.

    Google Scholar 

  128. Favre CJ, Mancuso M, Maas K et al. Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung. Am J Physiol Heart Circ Physiol 2003; 285 (5): H1917–38.

    Google Scholar 

  129. Feldheim DA, Kim YI, Bergemann AD et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 2000; 25 (3): 563–74.

    Google Scholar 

  130. Feng G, Laskowski MB, Feldheim DA et al. Roles for ephrins in positionally selective synaptogenesis between motor neurons and muscle fibers. Neuron 2000; 25 (2): 295–306.

    Google Scholar 

  131. Lyckman AW, Jhaveri S, Feldheim DA et al. Enhanced plasticity of retinothalamic projections in an ephrin-A2/A5 double mutant. J Neurosci 2001; 21 (19): 7684–90.

    Google Scholar 

  132. Cutforth T, Moring L, Mendelsohn M et al. Axonal ephrin-As and odorant receptors: Coordinate determination of the olfactory sensory map. Cell 2003; 114 (3): 311–22.

    Google Scholar 

  133. Frisen J, Yates PA, McLaughlin T et al. Ephrin-A5 (AL-1/ RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 1998; 20 (2): 235–43.

    Google Scholar 

  134. Prakash N, Vanderhaeghen P, Cohen-Cory S et al. Malformation of the functional organization of somatosensory cortex in adult ephrin-A5 knock-out mice revealed by in vivo functional imaging. J Neurosci 2000; 20 (15): 5841–7.

    Google Scholar 

  135. Yabuta NH, Butler AK, Callaway EM. Laminar specificity of local circuits in barrel cortex of ephrin-A5 knockout mice. J Neurosci 2000; 20 (15): RC88.

    Google Scholar 

  136. Knoll B, Zarbalis K, Wurst W et al. A role for the EphA family in the topographic targeting of vomeronasal axons. Development 2001; 128 (6): 895–906.

    Google Scholar 

  137. Uziel D, Muhlfriedel S, Zarbalis K et al. Miswiring of limbic thalamocortical projections in the absence of ephrin-A5. J Neurosci 2002; 22 (21): 9352–7.

    Google Scholar 

  138. Sturz A, Bader B, Thierauch KH et al. EphB4 signaling is capable of mediating ephrinB2-induced inhibition of cell migration. Biochem Biophys Res Commun 2004; 313 (1): 80–8.

    Google Scholar 

  139. Henkemeyer M, Itkis OS, Ngo M et al. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol 2003; 163 (6): 1313–26.

    Google Scholar 

  140. Howard MA, Rodenas-Ruano A, Henkemeyer M et al. Eph receptor deficiencies lead to altered cochlear function. Hear Res 2003; 178 (1–2): 118–30.

    Google Scholar 

  141. Williams SE, Mann F, Erskine L et al. Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 2003; 39 (6): 919–35.

    Google Scholar 

  142. Huynh-Do U, Stein E, Lane AA et al. Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. EMBO J 1999; 18 (8): 2165–73.

    Google Scholar 

  143. Hall SM, Hislop AA, Haworth SG. Origin, differentiation, and maturation of human pulmonary veins. Am J Respir Cell Mol Biol 2002; 26 (3): 333–40.

    Google Scholar 

  144. Steinle JJ, Meininger CJ, Forough R et al. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 2002; 277 (46): 43830–5.

    Google Scholar 

  145. Shimoyama M, Matsuoka H, Nagata A et al. Developmental expression of EphB6 in the thymus: Lessons from EphB6 knockout mice. Biochem Biophys Res Commun 2002; 298 (1): 87–94.

    Google Scholar 

  146. Yokoyama N, Romero MI, Cowan CA et al. Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron 2001; 29 (1): 85–97.

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Rhematology and Immunology, USA

    Dana M. Brantley-Sieders, Dana M. Brantley-Sieders & Jin Chen

  2. Department of Cancer Biology, USA

    Jin Chen

  3. Department of Cell and Developmental Biology, USA

    Jin Chen

  4. Vanderbilt University School of Medicine, A-4323 MCN, 1161 21st Avenue South, Nashville, TN, 37232-2363, USA

    Jin Chen

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  1. Dana M. Brantley-Sieders
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  2. Jin Chen
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Brantley-Sieders, D.M., Chen, J. Eph Receptor Tyrosine Kinases in Angiogenesis: From Development to Disease. Angiogenesis 7, 17–28 (2004). https://doi.org/10.1023/B:AGEN.0000037340.33788.87

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