Therapeutic targeting of EPH receptors and their ligands

Nature Reviews Drug Discovery

Volumn 13, Issue 1, 2014, Pages 39-62

  Boyd, Andrew W ^a   Bartlett, Perry F ^b   Lackmann, Martin ^c  

^a QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^b UNIVERSITY OF QUEENSLAND   (Australia)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BAFETINIB; BCR ABL PROTEIN; BEVACIZUMAB; BOSUTINIB; CARBOPLATIN; DASATINIB; DENDRITIC CELL VACCINE; EPHRIN B2; EPHRIN RECEPTOR; EPHRIN RECEPTOR B4; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERLOTINIB; IMMUNOGLOBULIN G1 ANTIBODY; JI 101; JL 101; KB 004; MEDI 547; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY 1C1; MONOCLONAL ANTIBODY 2H9; NILOTINIB; PACLITAXEL; PLATELET DERIVED GROWTH FACTOR RECEPTOR; RITUXIMAB; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY; SMALL INTERFERING RNA; TRASTUZUMAB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN RECEPTOR 2; XL 647;

ANTINEOPLASTIC ACTIVITY; BLEEDING; BLOOD CLOTTING DISORDER; CANCER INHIBITION; CANCER RESEARCH; CARCINOGENESIS; CLINICAL TRIAL (TOPIC); COLON CANCER; DRUG PROTEIN BINDING; DRUG RECEPTOR BINDING; DRUG RESEARCH; DRUG TARGETING; ENDOMETRIUM CANCER; ENDOMETRIUM CARCINOMA; FOLLICULAR LYMPHOMA; GLIOBLASTOMA; GLIOMA; HEMATOLOGIC MALIGNANCY; HUMAN; LUNG NON SMALL CELL CANCER; METASTASIS INHIBITION; METASTATIC MELANOMA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN METHYLATION; PROTEIN SYNTHESIS INHIBITION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; SQUAMOUS CELL CARCINOMA; UNSPECIFIED SIDE EFFECT;

EID: 84891703635     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4175     Document Type: Review

References (305)

1. Pasquale, E. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nature Rev. Cancer 10, 165-180 (2010).
2. Lackmann, M. & Boyd, A. W. Eph, a protein family coming of age: more confusion, insight, or complexity? Sci. Signal. 1, re2 (2008).
3. Janes, P. W., Adikari, S. & Lackmann, M. Eph/ephrin signalling and function in oncogenesis: lessons from embryonic development. Curr. Cancer Drug Targets 8, 473-479 (2008).
4. Daar, I. O. Non-SH2/PDZ reverse signaling by ephrins. Semin. Cell Dev. Biol. 23, 65-74 (2012).
5. Davy, A. & Soriano, P. Ephrin signaling in vivo: look both ways. Dev. Dyn. 232, 1-10 (2005). (Pubitemid 40070853)
6. Janes, P. W., Nievergall, E. & Lackmann, M. Concepts and consequences of Eph receptor clustering. Semin. Cell Dev. Biol. 23, 43-50 (2012).
7. Arvanitis, D. & Davy, A. Eph/ephrin signaling: networks. Genes Dev. 22, 416-429 (2008). (Pubitemid 351272750)
8. Pitulescu, M. E. & Adams, R. H. Eph/ephrin molecules-a hub for signaling and endocytosis. Genes Dev. 24, 2480-2492 (2010).
9. Nievergall, E., Lackmann, M. & Janes, P. W. Eph-dependent cell-cell adhesion and segregation in development and cancer. Cell. Mol. Life Sci. 69, 1813-1843 (2012).
10. Batlle, E. & Wilkinson, D. G. Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis. Cold Spring Harb. Perspect. Biol. 4, a008227 (2012).
11. Poliakov, A., Cotrina, M. & Wilkinson, D. G. Diverse roles of Eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev. Cell 7, 465-480 (2004). (Pubitemid 39341833)
12. Genander, M. & Frisen, J. Ephrins and Eph receptors in stem cells and cancer. Curr. Opin. Cell Biol. 22, 611-616 (2010).
13. Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741-753 (1998). (Pubitemid 28257581)
14. Gerety, S. S., Wang, H. U., Chen, Z. F. & Anderson, D. J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403-414 (1999). (Pubitemid 29499793)
15. Adams, R. H. et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295-306 (1999). (Pubitemid 29095801)
16. Compagni, A., Logan, M., Klein, R. & Adams, R. H. Control of skeletal patterning by ephrinB1-EphB interactions. Dev. Cell 5, 217-230 (2003). (Pubitemid 37006467)
17. Davy, A., Aubin, J. & Soriano, P. Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev. 18, 572-583 (2004). (Pubitemid 38372813)
18. Dottori, M. et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Natl Acad. Sci. USA 95, 13248-13253 (1998). (Pubitemid 28509557)
19. Kullander, K. et al. Role of EphA4 and EphrinB3 in local neuronal circuits that control walking. Science 299, 1889-1892 (2003). (Pubitemid 36358203)
20. Gallarda, B. W. et al. Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320, 233-236 (2008). (Pubitemid 351521419)
21. Du, J., Fu, C. & Sretavan, D. W. Eph/ephrin signaling as a potential therapeutic target after central nervous system injury. Curr. Pharm. Des. 13, 2507-2518 (2007). (Pubitemid 47423677)
22. Klein, R. Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nature Neurosci. 12, 15-20 (2009).
23. Matsuo, K. Eph and ephrin interactions in bone. Adv. Exp. Med. Biol. 658, 95-103 (2010).
24. Salvucci, O. & Tosato, G. Essential roles of EphB receptors and EphrinB ligands in endothelial cell function and angiogenesis. Adv. Cancer Res. 114, 21-57 (2012).
25. Merlos-Suarez, A. & Batlle, E. Eph-Ephrin signalling in adult tissues and cancer. Curr. Opin. Cell Biol. 20, 194-200 (2008).
26. Brantley-Sieders, D. M. et al. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J. Clin. Invest. 118, 64-78 (2008).
27. Noren, N. K. & Pasquale, E. B. Paradoxes of the EphB4 receptor in cancer. Cancer Res. 67, 3994-3997 (2007). (Pubitemid 46815041)
28. Pasquale, E. B. Eph-ephrin bidirectional signaling in physiology and disease. Cell 133, 38-52 (2008). (Pubitemid 351442996)
29. Astin, J. W. et al. Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nature Cell Biol. 12, 1194-1204 (2010).
30. Carvalho, R. F. et al. Silencing of EphA3 through a cis interaction with ephrinA5. Nature Neurosci. 9, 322-330 (2006). (Pubitemid 43290961)
31. Kao, T. J. & Kania, A. Ephrin-mediated cis-attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron 71, 76-91 (2011).
32. Marquardt, T. et al. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 121, 127-139 (2005).
33. Carter, N., Nakamoto, T., Hirai, H. & Hunter, T. EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nature Cell Biol. 4, 565-573 (2002).
34. Miao, H., Burnett, E., Kinch, M., Simon, E. & Wang, B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature Cell Biol. 2, 62-69 (2000).
35. Miao, H. et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nature Cell Biol. 3, 527-530 (2001). (Pubitemid 32422092)
36. Kumar, S. R. et al. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res. 69, 3736-3745 (2009).
37. Noren, N. K., Foos, G., Hauser, C. A. & Pasquale, E. B. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nature Cell Biol. 8, 815-825 (2006). (Pubitemid 44151584)
38. Wang, S. D. et al. EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase. Oncogene 31, 5132-5143 (2012).
39. Batlle, E. et al. EphB receptor activity suppresses colorectal cancer progression. Nature 435, 1126-1130 (2005). (Pubitemid 40910522)
40. Merlos-Suarez, A. et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8, 511-524 (2011).
41. Genander, M. et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 139, 679-692 (2009).
42. Holmberg, J. et al. EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125, 1151-1163 (2006). (Pubitemid 43866196)
43. Chumley, M. J., Catchpole, T., Silvany, R. E., Kernie, S. G. & Henkemeyer, M. EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis. J. Neurosci. 27, 13481-13490 (2007). (Pubitemid 350255330)
44. Bush, J. O. & Soriano, P. Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Genes Dev. 24, 2068-2080 (2010).
45. Depaepe, V. et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 435, 1244-1250 (2005). (Pubitemid 40943090)
46. Holmberg, J. et al. Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev. 19, 462-471 (2005). (Pubitemid 40256278)
47. Jiao, J. W., Feldheim, D. A. & Chen, D. F. Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system. Proc. Natl Acad. Sci. USA 105, 8778-8783 (2008). (Pubitemid 351987756)
48. Day, B. W. et al. EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell 23, 238-248 (2013).
49. Truitt, L. & Freywald, A. Dancing with the dead: Eph receptors and their kinase-null partners. Biochem. Cell Biol. 89, 115-129 (2011).
50. Kullander, K. et al. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29, 73-84 (2001). (Pubitemid 32108723)
51. Birgbauer, E., Cowan, C. A., Sretavan, D. W. & Henkemeyer, M. Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development 127, 1231-1241 (2000). (Pubitemid 30179513)
52. Grunwald, I. C. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027-1040 (2001). (Pubitemid 34075394)
53. Gu, C. & Park, S. The EphA8 receptor regulates integrin activity through p110γ phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner. Mol. Cell. Biol. 21, 4579-4597 (2001). (Pubitemid 32588241)
54. Matsuoka, H., Obama, H., Kelly, M. L., Matsui, T. & Nakamoto, M. Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration. J. Biol. Chem. 280, 29355-29363 (2005). (Pubitemid 41161391)
55. Wimmer-Kleikamp, S. H. et al. Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells. Blood 112, 721-732 (2008).
56. Solanas, G., Cortina, C., Sevillano, M. & Batlle, E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nature Cell Biol. 13, 1100-1107 (2011).
57. Davy, A. et al. Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev. 13, 3125-3135 (1999). (Pubitemid 30016112)
58. Gauthier, L. R. & Robbins, S. M. Ephrin signaling: one raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them? Life Sci. 74, 207-216 (2003). (Pubitemid 37357052)
59. Holmberg, J., Clarke, D. L. & Frisen, J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408, 203-206 (2000).
60. Twigg, S. R. et al. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc. Natl Acad. Sci. USA 101, 8652-8657 (2004). (Pubitemid 38745826)
61. Davy, A., Bush, J. O. & Soriano, P. Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol. 4, e315 (2006).
62. Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487-491 (2010).
63. Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483-486 (2010).
64. Meima, L. et al. AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton. Eur. J. Neurosci. 9, 177-188 (1997).
65. Salaita, K. et al. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 327, 1380-1385 (2010).
66. Mellitzer, G., Xu, Q. & Wilkinson, D. G. Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77-81 (1999). (Pubitemid 29315114)
67. Lawrenson, I. D. et al. Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3- expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. J. Cell Sci. 115, 1059-1072 (2002). (Pubitemid 34257389)
68. Hansen, M. J., Dallal, G. E. & Flanagan, J. G. Retinal axon response to ephrin-as shows a graded, concentration-dependent transition from growth promotion to inhibition. Neuron 42, 717-730 (2004). (Pubitemid 38748787)
69. Cortina, C. et al. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nature Genet. 39, 1376-1383 (2007). (Pubitemid 350034995)
70. Noren, N. K., Yang, N. Y., Silldorff, M., Mutyala, R. & Pasquale, E. B. Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor. Biochem. J. 422, 433-442 (2009).
71. Watanabe, T. & Takahashi, Y. Tissue morphogenesis coupled with cell shape changes. Curr. Opin. Genet. Dev. 20, 443-447 (2010).
72. Flanagan, J. G. Neural map specification by gradients. Curr. Opin. Neurobiol. 16, 59-66 (2006). (Pubitemid 43221854)
73. Adams, R. H. & Eichmann, A. Axon guidancemolecules in vascular patterning. Cold Spring Harb. Perspect. Biol. 2, a001875 (2010).
74. Matsuo, K. & Otaki, N. Bone cell interactions through Eph/ephrin: bone modeling, remodeling and associated diseases. Cell Adh. Migr. 6, 148-156 (2012).
75. Filosa, A. et al. Neuron-glia communication via EphA4/ephrin-A3 modulates LTP through glial glutamate transport. Nature Neurosci. 12, 1285-1292 (2009).
76. Erber, R. et al. EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J. 25, 628-641 (2006). (Pubitemid 43237669)
77. Salvucci, O. et al. EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures. Blood 114, 1707-1716 (2009).
78. Zhao, C. et al. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell. Metab. 4, 111-121 (2006). (Pubitemid 44138718)
79. Fang, Y. et al. Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells 31, 349-359 (2013).
80. Nomura, T., Göritz, C., Catchpole, T., Henkemeyer, M. & Frisén, J. EphB signaling controls lineage plasticity of adult neural stem cell niche cells. Cell Stem Cell 7, 730-743 (2010).
81. Genander, M., Holmberg, J. & Frisen, J. Ephrins negatively regulate cell proliferation in the epidermis and hair follicle. Stem Cells 28, 1196-1205 (2010).
82. Batlle, E. et al. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251-263 (2002). (Pubitemid 35292445)
83. Jung, P. et al. Isolation and in vitro expansion of human colonic stem cells. Nature Med. 17, 1225-1227 (2011).
84. Wykosky, J. & Debinski, W. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting. Mol. Cancer Res. 6, 1795-1806 (2008).
85. Keane, N., Freeman, C., Swords, R. & Giles, F. J. EPHA3 as a novel therapeutic target in the hematological malignancies. Expert Rev. Hematol. 5, 325-340 (2012).
86. Ashida, S. et al. Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs. Cancer Res. 64, 5963-5972 (2004). (Pubitemid 39129392)
87. Oki, M. et al. Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. World J. Gastroenterol. 14, 5650-5656 (2008).
88. Oricchio, E. & Wendel, H. G. Mining the cancer genome uncovers therapeutic activity of EphA7 against lymphoma. Cell Cycle 11, 1076-1080 (2012).
89. Fox, B. P. & Kandpal, R. P. EphB6 receptor significantly alters invasiveness and other phenotypic characteristics of human breast carcinoma cells. Oncogene 28, 1706-1713 (2009).
90. Brantley-Sieders, D. M. et al. Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS ONE 6, e24426 (2011).
91. Ganju, P., Shigemoto, K., Brennan, J., Entwistle, A. & Reith, A. D. The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development. Oncogene 9, 1613-1624 (1994). (Pubitemid 24163387)
92. Ireton, R. C. & Chen, J. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr. Cancer Drug Targets 5, 149-157 (2005). (Pubitemid 40694857)
93. Brantley-Sieders, D. M. et al. EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J. Cell Sci. 117, 2037-2049 (2004). (Pubitemid 38745137)
94. Brantley-Sieders, D. M. et al. Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J. 19, 1884-1886 (2005). (Pubitemid 41598783)
95. Fang, W. B., Brantley-Sieders, D. M., Parker, M. A., Reith, A. D. & Chen, J. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene 24, 7859-7868 (2005). (Pubitemid 41715192)
96. Ogawa, K. et al. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19, 6043-6052 (2000). (Pubitemid 32039378)
97. Zelinski, D. P., Zantek, N. D., Stewart, J. C., Irizarry, A. R. & Kinch, M. S. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 61, 2301-2306 (2001). (Pubitemid 32692063)
98. Wu, Q. et al. Expression of Ephb2 and Ephb4 in breast carcinoma. Pathol. Oncol. Res. 10, 26-33 (2004). (Pubitemid 38506609)
99. Kumar, S. R. et al. Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am. J. Pathol. 169, 279-293 (2006).
100. Hochgrafe, F. et al. Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells. Cancer Res. 70, 9391-99401 (2010).
101. Parri, M., Taddei, M. L., Bianchini, F., Calorini, L. & Chiarugi, P. EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res. 69, 2072-2081 (2009).
102. Udayakumar, D. et al. EphA2 is a critical oncogene in melanoma. Oncogene 30, 4921-4929 (2011).
103. Noren, N. K., Lu, M., Freeman, A. L., Koolpe, M. & Pasquale, E. B. Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc. Natl Acad. Sci. USA 101, 5583-5588 (2004). (Pubitemid 38481199)
104. Xiao, Z. et al. EphB4 promotes or suppresses Ras/MEK/ERK pathway in a context-dependent manner: Implications for EphB4 as a cancer target. Cancer Biol. Ther. 13, 630-637 (2012).
105. Dopeso, H. et al. The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis. Cancer Res. 69, 7430-7438 (2009).
106. Jubb, A. M. et al. EphB2 is a prognostic factor in colorectal cancer. Clin. Cancer Res. 11, 5181-5187 (2005). (Pubitemid 41003704)
107. Herath, N. I. et al. Complex expression patterns of Eph receptor tyrosine kinases and their ephrin ligands in colorectal carcinogenesis. Eur. J. Cancer 48, 753-762 (2012).
108. Chiari, R. et al. Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res. 60, 4855-4863 (2000).
109. Xi, H. Q. & Zhao, P. Clinicopathological significance and prognostic value of EphA3 and CD133 expression in colorectal carcinoma. J. Clin Pathol. 64, 498-503 (2011).
110. Zhuang, G. et al. Effects of cancer-associated EPHA3 mutations on lung cancer. J. Natl Cancer Inst. 104, 1182-1197 (2012).
111. Binda, E. et al. The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell 22, 765-780 (2012).
112. Ashton, J. M. et al. Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells. Cell Stem Cell 11, 359-372 (2012).
113. Boyd, A. W. et al. Isolation and characterization of a novel receptor-type protein tyrosine kinase (hek) from a human pre-B cell line. J. Biol. Chem. 267, 3262-3267 (1992).
114. Hagey, A. et al. A recombinant antibody to EphA3 for the treatment of hematologic malignancies: research update and interim Phase 1 study results. Blood (ASH Annual Meeting Abstracts) 118, 4893 (2011).
115. Xia, G. et al. EphB4 expression and biological significance in prostate cancer. Cancer Res. 65, 4623-4632 (2005). (Pubitemid 40740798)
116. Berclaz, G. et al. Activation of the receptor protein tyrosine kinase EphB4 in endometrial hyperplasia and endometrial carcinoma. Ann. Oncol. 14, 220-226 (2003). (Pubitemid 36305433)
117. Ronsch, K. et al. Class I and III HDACs and loss of active chromatin features contribute to epigenetic silencing of CDX1 and EPHB tumor suppressor genes in colorectal cancer. Epigenetics 6, 610-622 (2011).
118. Guo, H. et al. Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res. 66, 7050-7058 (2006). (Pubitemid 44197681)
119. Oricchio, E. et al. The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147, 554-564 (2011).
120. Miao, H. et al. 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 (2009).
121. Macrae, M. et al. A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell 8, 111-118 (2005). (Pubitemid 41132740)
122. Dawson, D. W. et al. Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas. Oncogene 26, 4243-4252 (2007). (Pubitemid 46975800)
123. Wang, J. et al. Downregulation of EphA7 by hypermethylation in colorectal cancer. Oncogene 24, 5637-5647 (2005). (Pubitemid 43119357)
124. Wang, J. et al. Differential expression of EphA7 receptor tyrosine kinase in gastric carcinoma. Hum. Pathol. 38, 1649-1656 (2007). (Pubitemid 47589087)
125. Guan, M., Xu, C., Zhang, F. & Ye, C. Aberrant methylation of EphA7 in human prostate cancer and its relation to clinicopathologic features. Int. J. Cancer 124, 88-94 (2009).
126. Alazzouzi, H. et al. Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Res. 65, 10170-10173 (2005). (Pubitemid 41743705)
127. Dottori, M., Down, M., Huttmann, A., Fitzpatrick, D. R. & Boyd, A. W. Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells. Blood 94, 2477-2486 (1999). (Pubitemid 29467697)
128. Kuang, S. Q. et al. Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia. Blood 115, 2412-2419 (2010).
129. Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274 (2006). (Pubitemid 44571966)
130. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069-1075 (2008).
131. Balakrishnan, A. et al. Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res. 67, 3545-3550 (2007). (Pubitemid 46762135)
132. Bonifaci, N. et al. Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. PLoS ONE 5, e14078 (2010).
133. Lisabeth, E. M., Fernandez, C. & Pasquale, E. B. Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms. Biochemistry 51, 1464-1475 (2012).
134. Nievergall, E., Saunders, T. & Lackmann, M. Targeting of EPH receptor tyrosine kinases for anticancer therapy. Crit. Rev. Oncog. 17, 211-232 (2012).
135. Hunter, S. G. et al. Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Mol. Cell. Biol. 26, 4830-4842 (2006). (Pubitemid 43955801)
136. Carles-Kinch, K., Kilpatrick, K. E., Stewart, J. C. & Kinch, M. S. Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer Res. 62, 2840-2847 (2002). (Pubitemid 34525769)
137. Landen, C. N. Jr et al. Efficacy and antivascular effects of EphA2 reduction with an agonistic antibody in ovarian cancer. J. Natl Cancer Inst. 98, 1558-1570 (2006).
138. Gokmen-Polar, Y. et al. Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer. Breast Cancer Res. Treat. 127, 375-384 (2011).
139. Zhuang, G. et al. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res. 70, 299-308 (2010).
140. Jackson, D. et al. A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res. 68, 9367-9374 (2008).
141. Lee, J. W. et al. EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma. J. Natl Cancer Inst. 101, 1193-1205 (2009).
142. Lee, J. W. et al. EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin. Cancer Res. 16, 2562-2570 (2010).
143. Annunziata, C. M. et al. Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Invest. New Drugs 31, 77-84 (2013).
144. Mao, W. et al. EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer. Cancer Res. 64, 781-788 (2004). (Pubitemid 38176871)
145. Salvucci, O., de la Luz Sierra, M., Martina, J. A., McCormick, P. J. & Tosato, G. EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood 108, 2914-2922 (2006).
146. Kertesz, N. et al. The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth. Blood 107, 2330-2338 (2006). (Pubitemid 43345552)
147. Martiny-Baron, G. et al. Inhibition of tumor growth and angiogenesis by soluble EphB4. Neoplasia 6, 248-257 (2004). (Pubitemid 38657081)
148. Krasnoperov, V. et al. Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth. Am. J. Pathol. 176, 2029-2038 (2010).
149. Abengozar, M. A. et al. Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth. Blood 119, 4565-4576 (2012).
150. Vearing, C. et al. 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, 6745-6754 (2005). (Pubitemid 41060712)
151. Palath, V. et al. A recombinant antibody to EphA3 with pro-apoptotic and enhanced ADCC activity against various hematologic malignancies shows selective inhibition of colony formation from long-term culture-initiating cells (LTC-ICs) in primary leukemia samples. Blood (ASH Annual Meeting Abstracts) 116, 2897 (2010).
152. Heroult, M. et al. EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell-expressed ephrinB2. Mol. Cancer Res. 8, 1297-1309 (2010).
153. Scehnet, J. S. et al. The role of Ephs, Ephrins, and growth factors in Kaposi sarcoma and implications of EphrinB2 blockade. Blood 113, 254-263 (2009).
154. Djokovic, D. et al. Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer 10, 641 (2010).
155. Dobrzanski, P. et al. Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res. 64, 910-919 (2004). (Pubitemid 38176892)
156. Wykosky, J. et al. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene 27, 7260-7273 (2008).
157. Noblitt, L. W., Bangari, D. S., Shukla, S., Mohammed, S. & Mittal, S. K. Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy. Cancer Gene Ther. 12, 46-53 (2005). (Pubitemid 39665242)
158. Wykosky, J., Gibo, D. M. & Debinski, W. A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor expressing tumor cells. Mol. Cancer Ther. 6, 3208-3218 (2007).
159. Sun, X. L. et al. Molecular targeting of malignant glioma cells with an EphA2-specific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells. Cancer Lett. 312, 168-177 (2011).
160. Noberini, R. et al. A disalicylic acid-furanyl derivative inhibits ephrin binding to a subset of Eph receptors. Chem. Biol. Drug Des. 78, 667-678 (2011).
161. Noberini, R. et al. Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J. Biol. Chem. 283, 29461-29472 (2008).
162. Giorgio, C. et al. Lithocholic acid is an Eph-ephrin ligand interfering with Eph-kinase activation. PLoS ONE 6, e18128 (2011).
163. Chaudhari, A. et al. Cupredoxin-cancer interrelationship: azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth. Biochemistry 46, 1799-1810 (2007).
164. Gendreau, S. B. et al. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin. Cancer Res. 13, 3713-3723 (2007). (Pubitemid 46955136)
165. Wakelee, H. A. et al. A phase I dose-escalation and pharmacokinetic (PK) study of a novel spectrum selective kinase inhibitor, XL647, in patients with advanced solid malignancies (ASM). J. Clin. Oncol. 24, Abstr. 3044 (2006).
166. Pietanza, M. C. et al. XL647-a multitargeted tyrosine kinase inhibitor: results of a phase II study in subjects with non-small cell lung cancer who have progressed after responding to treatment with either gefitinib or erlotinib. J. Thorac. Oncol. 7, 219-226 (2012).
167. Pietanza, M. C. et al. Phase II study of the multitargeted tyrosine kinase inhibitor XL647 in patients with non-small-cell lung cancer. J. Thorac. Oncol. 7, 856-865 (2012).
168. Gnoni, A., Marech, I., Silvestris, N., Vacca, A. & Lorusso, V. Dasatinib: an anti-tumour agent via Src inhibition. Curr. Drug Targets 12, 563-578 (2011).
169. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotech. 25, 1035-1044 (2007). (Pubitemid 47517638)
170. Melnick, J. S. et al. An efficient rapid system for profiling the cellular activities of molecular libraries. Proc. Natl Acad. Sci. USA 103, 3153-3158 (2006). (Pubitemid 43346440)
171. Huang, F. et al. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res. 67, 2226-2238 (2007). (Pubitemid 46424242)
172. Chang, Q., Jorgensen, C., Pawson, T. & Hedley, D. W. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer. Br. J. Cancer 99, 1074-1082 (2008).
173. Farenc, C., Celie, P. H., Tensen, C. P., de Esch, I. J. & Siegal, G. Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state. FEBS Lett. 585, 3593-3599 (2011).
174. Kluger, H. M. et al. A phase 2 trial of dasatinib in advanced melanoma. Cancer 117, 2202-2208 (2011).
175. Rix, U. et al. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia 24, 44-50 (2010).
176. Bardelle, C. et al. Inhibitors of the tyrosine kinase EphB4. Part 1: structure-based design and optimization of a series of 2,4-bis- anilinopyrimidines. Bioorg. Med. Chem. Lett. 18, 2776-2780 (2008). (Pubitemid 351622047)
177. Choi, Y. et al. Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors. Bioorg. Med. Chem. Lett. 19, 4467-4470 (2009).
178. Martiny-Baron, G. et al. The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis. Angiogenesis 13, 259-267 (2010).
179. Thaker, P. H. et al. EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin. Cancer Res. 10, 5145-5150 (2004). (Pubitemid 39099789)
180. Landen, C. N. et al. Intraperitoneal delivery of liposomal siRNA for therapy of advanced ovarian cancer. Cancer Biol. Ther. 5, 1708-1713 (2006).
181. Jin, M. et al. Erythropoietin-producing hepatocyte B6 variant-derived peptides with the ability to induce glioma-reactive cytotoxic T lymphocytes in human leukocyte antigen-A2+ glioma patients. Cancer Sci. 99, 1656-1662 (2008).
182. Yamaguchi, S. et al. Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity. Cancer Immunol. Immunother. 57, 1861-1869 (2008).
183. Okada, H. et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with α-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29, 330-336 (2011).
184. Xiong, C. et al. In vivo small-animal PET/CT of EphB4 receptors using 64Cu-labeled peptide. J. Nucl. Med. 52, 241-248 (2011).
185. Cai, W., Chen, K., Li, Z. B., Gambhir, S. S. & Chen, X. Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J. Nucl. Med. 48, 1862-1870 (2007). (Pubitemid 350099333)
186. Zhang, R. et al. Peptide-conjugated polymeric micellar nanoparticles for Dual SPECT and optical imaging of EphB4 receptors in prostate cancer xenografts. Biomaterials 32, 5872-5879 (2011).
187. Cuny, G. D. Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. Curr. Pharm. Des. 15, 3919-3939 (2009).
188. Goldshmit, Y., McLenachan, S. & Turnley, A. Roles of Eph receptors and ephrins in the normal and damaged adult CNS. Brain Res. Rev. 52, 327-345 (2006). (Pubitemid 44291808)
189. Murai, K. K. & Pasquale, E. B. Eph receptors and ephrins in neuron-astrocyte communication at synapses. Glia 59, 1567-1578 (2011).
190. Chen, Y., Fu, A. K. & Ip, N. Y. Eph receptors at synapses: implications in neurodegenerative diseases. Cell Signal. 24, 606-611 (2012).
191. Attwood, B. K. et al. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 473, 372-375 (2011).
192. Simon, A. M. et al. Early changes in hippocampal Eph receptors precede the onset of memory decline in mouse models of Alzheimer's disease. J. Alzheimers Dis. 17, 773-786 (2009).
193. Cisse, M. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47-52 (2011).
194. Biervert, C., Horvath, E. & Fahrig, T. Semiquantitative expression analysis of ephrine-receptor tyrosine kinase mRNA's in a rat model of traumatic brain injury. Neurosci. Lett. 315, 25-28 (2001). (Pubitemid 33049990)
195. Theus, M. H., Ricard, J., Bethea, J. R. & Liebl, D. J. EphB3 limits the expansion of neural progenitor cells in the subventricular zone by regulating p53 during homeostasis and following traumatic brain injury. Stem Cells 28, 1231-1242 (2010).
196. Goldshmit, Y. & Bourne, J. Upregulation of EphA4 on astrocytes potentially mediates astrocytic gliosis after cortical lesion in the marmoset monkey. J. Neurotrauma 27, 1321-1332 (2010).
197. Frugier, T. et al. Expression and activation of EphA4 in the human brain after traumatic injury. J. Neuropathol. Exp. Neurol. 71, 242-250 (2012).
198. Hanell, A. et al. Functional and histological outcome after focal traumatic brain injury is not improved in conditional EphA4 knockout mice. J. Neurotrauma 29, 2660-2671 (2012).
199. Goldshmit, Y., Galea, M. P., Wise, G., Bartlett, P. F. & Turnley, A. M. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J. Neurosci. 24, 10064-10073 (2004). (Pubitemid 39492030)
200. Irizarry-Ramirez, M. et al. Upregulation of EphA3 receptor after spinal cord injury. J. Neurotrauma 22, 929-935 (2005). (Pubitemid 41153877)
201. Willson, C. A., Miranda, J. D., Foster, R. D., Onifer, S. M. & Whittemore, S. R. Transection of the adult rat spinal cord upregulates EphB3 receptor and ligand expression. Cell Transplant. 12, 279-290 (2003). (Pubitemid 36577005)
202. Fabes, J. et al. Accumulation of the inhibitory receptor EphA4 may prevent regeneration of corticospinal tract axons following lesion. Eur. J. Neurosci. 23, 1721-1730 (2006).
203. Dixon, K. J., Munro, K. M., Boyd, A. W., Bartlett, P. F. & Turnley, A. M. Partial change in EphA4 knockout mouse phenotype: loss of diminished GFAP upregulation following spinal cord injury. Neurosci. Lett. 525, 66-71 (2012).
204. Herrmann, J. E., Shah, R. R., Chan, A. F. & Zheng, B. EphA4 deficient mice maintain astroglial-fibrotic scar formation after spinal cord injury. Exp. Neurol. 223, 582-598 (2010).
205. Duffy, P. et al. Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury. Proc. Natl Acad. Sci. USA 109, 5063-5068 (2012).
206. Ren, Z. et al. Improved axonal regeneration after spinal cord injury in mice with conditional deletion of ephrin B2 under the GFAP promoter. Neuroscience 241, 89-99 (2013).
207. Bundesen, L. Q., Scheel, T. A., Bregman, B. S. & Kromer, L. F. Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J. Neurosci. 23, 7789-7800 (2003). (Pubitemid 37052347)
208. Goldshmit, Y. et al. EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice. PLoS ONE 6, e24636 (2011).
209. Spanevello, M. D. et al. Acute delivery of EphA4-Fc improves functional recovery after contusive spinal cord injury in rats. J. Neurotrauma 30, 1023-1034 (2013).
210. Fabes, J., Anderson, P., Brennan, C. & Bolsover, S. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord. Eur. J. Neurosci. 26, 2496-2505 (2007). (Pubitemid 350064163)
211. Noberini, R. et al. PEGylation potentiates the effectiveness of an antagonistic peptide that targets the EphB4 receptor with nanomolar affinity. PLoS ONE 6, e28611 (2011).
212. Figueroa, J. D. et al. Inhibition of EphA7 up-regulation after spinal cord injury reduces apoptosis and promotes locomotor recovery. J. Neurosci. Res. 84, 1438-1451 (2006). (Pubitemid 44683138)
213. Arocho, L. C. et al. Expression profile and role of EphrinA1 ligand after spinal cord injury. Cell. Mol. Neurobiol. 31, 1057-1069 (2011).
214. Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nature Genet. 43, 436-441 (2011).
215. Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nature Genet. 43, 429-435 (2011).
216. Lickliter, J. D., Smith, F. M., Olsson, J. E., Mackwell, K. L. & Boyd, A. W. Embryonic stem cells express multiple Eph-subfamily receptor tyrosine kinases. Proc. Natl Acad. Sci. USA 93, 145-150 (1996). (Pubitemid 26038117)
217. Sheffler-Collins, S. I. & Dalva, M. B. EphBs: an integral link between synaptic function and synaptopathies. Trends Neurosci. 35, 293-304 (2012).
218. Litterst, C. et al. Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J. Biol. Chem. 282, 16155-16163 (2007). (Pubitemid 47100347)
219. Inoue, E. et al. Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. J. Cell Biol. 185, 551-564 (2009).
220. Matsui, C. et al. Involvement of the gamma-secretase-mediated EphA4 signaling pathway in synaptic pathogenesis of Alzheimer's disease. Brain Pathol. 22, 776-787 (2012).
221. Sobel, R. A. Ephrin A receptors and ligands in lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol. 15, 35-45 (2005). (Pubitemid 40224065)
222. Varade, J. et al. Replication study of 10 genes showing evidence for association with multiple sclerosis: validation of TMEM39A, IL12B and CBLB [correction of CLBL] genes. Mult. Scler. 18, 959-965 (2012).
223. Munro, K. M. et al. EphA4 receptor tyrosine kinase is a modulator of onset and disease severity of experimental autoimmune encephalomyelitis. PLoS ONE 8, e55948 (2013).
224. Lin, L., Lesnick, T. G., Maraganore, D. M. & Isacson, O. Axon guidance and synaptic maintenance: preclinical markers for neurodegenerative disease and therapeutics. Trends Neurosci. 32, 142-149 (2009).
225. Jing, X. et al. Ephrin-A1-mediated dopaminergic neurogenesis and angiogenesis in a rat model of Parkinson's disease. PLoS ONE 7, e32019 (2012).
226. Tsuda, H. et al. The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell 133, 963-977 (2008). (Pubitemid 351787741)
227. Lua, S. et al. Structural, stability, dynamic and binding properties of the ALS-causing T46I mutant of the hVAPB MSP domain as revealed by NMR and MD simulations. PLoS ONE 6, e27072 (2011).
228. Van Hoecke, A. et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nature Med. 18, 1418-1422 (2012).
229. Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264, 1772-1775 (1994).
230. Coulthard, M. G. et al. Eph/Ephrin signaling in injury and inflammation. Am. J. Pathol. 181, 1493-1503 (2012).
231. Ivanov, A. I. & Romanovsky, A. A. Putative dual role of ephrin-Eph receptor interactions in inflammation. IUBMB Life 58, 389-394 (2006).
232. Lazarova, P. et al. Growth factor receptors in hematopoietic stem cells: EPH family expression in CD34+ and CD133+ cell populations from mobilized peripheral blood. Int. J. Immunopathol. Pharmacol. 19, 49-56 (2006).
233. Prevost, N. et al. Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets. Proc. Natl Acad. Sci. USA 102, 9820-9825 (2005). (Pubitemid 40993651)
234. Alfaro, D. et al. The Eph/ephrinB signal balance determines the pattern of T-cell maturation in the thymus. Immunol. Cell Biol. 89, 844-852 (2011).
235. Luo, H., Yu, G., Tremblay, J. & Wu, J. EphB6-null mutation results in compromised T cell function. J. Clin. Invest. 114, 1762-1773 (2004). (Pubitemid 40385532)
236. Kuijper, S., Turner, C. J. & Adams, R. H. Regulation of angiogenesis by Eph-ephrin interactions. Trends Cardiovasc. Med. 17, 145-151 (2007). (Pubitemid 46898841)
237. Holzman, L. B., Marks, R. M. & Dixit, V. M. A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Mol. Cell. Biol. 10, 5830-5838 (1990).
238. Pandey, A., Shao, H., Marks, R. M., Polverini, P. J. & Dixit, V. M. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-α-induced angiogenesis. Science 268, 567-569 (1995).
239. Chan, B. & Sukhatme, V. P. Receptor tyrosine kinase EphA2 mediates thrombin-induced upregulation of ICAM-1 in endothelial cells in vitro. Thromb. Res. 123, 745-752 (2009).
240. Funk, S. D. et al. EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 32, 686-695 (2012).
241. Fang, W. B. et al. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J. Cell Sci. 121, 358-368 (2008). (Pubitemid 351356707)
242. Zhou, N. et al. Inactivation of EphA2 promotes tight junction formation and impairs angiogenesis in brain endothelial cells. Microvasc. Res. 82, 113-121 (2011).
243. Thundyil, J. et al. Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE 8, e53528 (2013).
244. Baldwin, C. et al. Upregulation of EphA2 during in vivo and in vitro renal ischemia-reperfusion injury: role of Src kinases. Am. J. Physiol. Renal Physiol. 291, F960-F971 (2006). (Pubitemid 44772029)
245. Dries, J. L., Kent, S. D. & Virag, J. A. Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice. J. Physiol. 589, 1725-1740 (2011).
246. Cercone, M. A., Schroeder, W., Schomberg, S. & Carpenter, T. C. EphA2 receptor mediates increased vascular permeability in lung injury due to viral infection and hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L856-L863 (2009).
247. Adams, R. H. & Klein, R. Eph receptors and ephrin ligands. essential mediators of vascular development. Trends Cardiovasc. Med. 10, 183-188 (2000). (Pubitemid 32229885)
248. Bochenek, M. L., Dickinson, S., Astin, J. W., Adams, R. H. & Nobes, C. D. Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J. Cell Sci. 123, 1235-1246 (2010).
249. Pfaff, D. et al. Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes. J. Cell Sci. 121, 3842-3850 (2008).
250. Bonaparte, M. I. et al. Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus. Proc. Natl Acad. Sci. USA 102, 10652-10657 (2005). (Pubitemid 41061609)
251. Negrete, O. A. et al. EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 436, 401-405 (2005). (Pubitemid 41059050)
252. Tournoij, E. et al. The platelet P2Y12 receptor contributes to granule secretion through Ephrin A4 receptor. Platelets 23, 617-625 (2012).
253. Kitamura, T. et al. Enhancement of lymphocyte migration and cytokine production by ephrinB1 system in rheumatoid arthritis. Am. J. Physiol. Cell Physiol. 294, C189-C196 (2008).
254. Ivanov, A. I., Steiner, A. A., Scheck, A. C. & Romanovsky, A. A. Expression of Eph receptors and their ligands, ephrins, during lipopolysaccharide fever in rats. Physiol. Genom. 21, 152-160 (2005). (Pubitemid 40898475)
255. Sakamoto, A. et al. Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. J. Int. Med. Res. 39, 522-527 (2011).
256. Vihanto, M. M. et al. Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin. FASEB J. 19, 1689-1691 (2005). (Pubitemid 41429531)
257. Lin, S., Wang, B. & Getsios, S. Eph/ephrin signaling in epidermal differentiation and disease. Semin. Cell Dev. Biol. 23, 92-101 (2012).
258. Allan, E. H. et al. EphrinB2 regulation by PTH and PTHrP revealed by molecular profiling in differentiating osteoblasts. J. Bone Miner. Res. 23, 1170-1181 (2008). (Pubitemid 352040173)
259. Kwan Tat, S. et al. Activation of the receptor EphB4 by its specific ligand ephrin B2 in human osteoarthritic subchondral bone osteoblasts. Arthritis Rheum. 58, 3820-3830 (2008).
260. Vadivel, A. et al. Critical role of the axonal guidance cue EphrinB2 in lung growth, angiogenesis, and repair. Am. J. Respir. Crit. Care Med. 185, 564-574 (2012).
261. Reber, M., Burrola, P. & Lemke, G. A relative signalling model for the formation of a topographic neural map. Nature 431, 847-853 (2004). (Pubitemid 39434081)
262. Egea, J. & Klein, R. Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol. 17, 230-238 (2007). (Pubitemid 46679245)
263. Jorgensen, C. et al. Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells. Science 326, 1502-1509 (2009).
264. Wilkinson, D. G. How attraction turns to repulsion. Nature Cell Biol. 5, 851-853 (2003). (Pubitemid 37220684)
265. Janes, P. W. et al. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 123, 291-304 (2005). (Pubitemid 41457218)
266. Janes, P. W. et al. Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS Biol. 7, e1000215 (2009).
267. Janes, P. W. et al. Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors. J. Cell Biol. 195, 1033-1045 (2011).
268. Nievergall, E. et al. PTP1B regulates Eph receptor function and trafficking. J. Cell Biol. 191, 1189-1203 (2010).
269. Poliakov, A., Cotrina, M. L., Pasini, A. & Wilkinson, D. G. Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway. J. Cell Biol. 183, 933-947 (2008).
270. Shintani, T. et al. Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O. Nature Neurosci. 9, 761-769 (2006).
271. Hattori, M., Osterfield, M. & Flanagan, J. G. Regulated cleavage of a contact-mediated axon repellent. Science 289, 1360-1365 (2000). (Pubitemid 30656055)
272. Georgakopoulos, A. et al. Metalloproteinase/presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 25, 1242-1252 (2006).
273. Walker-Daniels, J., Riese, D. J. & Kinch, M. S. c-Cbl-dependent EphA2 protein degradation is induced by ligand binding. Mol. Cancer Res. 1, 79-87 (2002). (Pubitemid 36330213)
274. Holland, S. J. et al. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383, 722-725 (1996). (Pubitemid 26360649)
275. Ji, X. D. et al. EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res. 71, 1156-1166 (2011).
276. Makinen, T. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 19, 397-410 (2005). (Pubitemid 40189302)
277. Bush, J. O. & Soriano, P. Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev. 23, 1586-1599 (2009).
278. Li, J. J., Liu, D. P., Liu, G. T. & Xie, D. EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor. Oncogene 28, 1759-1768 (2009).
279. Wang, T. H., Chang, J. L., Ho, J. Y., Wu, H. C. & Chen, T. C. EphrinA5 suppresses colon cancer development by negatively regulating epidermal growth factor receptor stability. FEBS J. 279, 251-263 (2012).
280. Cowan, C. A. & Henkemeyer, M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413, 174-179 (2001). (Pubitemid 32867879)
281. Xu, N. J. & Henkemeyer, M. Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning. Nature Neurosci. 12, 268-276 (2009).
282. Bong, Y. S. et al. ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3. Proc. Natl Acad. Sci. USA 104, 17305-17310 (2007).
283. Lu, Q., Sun, E. E., Klein, R. S. & Flanagan, J. G. Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105, 69-79 (2001). (Pubitemid 32323917)
284. Lim, Y. S. et al. p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59, 746-758 (2008).
285. Tong, J., Elowe, S., Nash, P. & Pawson, T. Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity. J. Biol. Chem. 278, 6111-6119 (2003). (Pubitemid 36800863)
286. Larsen, A. B., Stockhausen, M. T. & Poulsen, H. S. Cell adhesion and EGFR activation regulate EphA2 expression in cancer. Cell Signal 22, 636-644 (2010).
287. Corrigan, C., Subramanian, R. & Miller, M. A. Eph and NMDA receptors control Ca2+/calmodulin-dependent protein kinase II activation during C. elegans oocyte meiotic maturation. Development 132, 5225-5237 (2005). (Pubitemid 43020177)
288. Huang, J. et al. EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells. Oncogene http://dx.doi.org/10.1038/onc.2013.238 (2013).
289. Foo, S. S. et al. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124, 161-173 (2006). (Pubitemid 43069317)
290. Hayashi, S., Asahara, T., Masuda, H., Isner, J. M. & Losordo, D. W. Functional ephrin-B2 expression for promotive interaction between arterial and venous vessels in postnatal neovascularization. Circulation 111, 2210-2218 (2005). (Pubitemid 40632437)
291. Foubert, P. et al. PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells. J. Clin. Invest. 117, 1527-1537 (2007). (Pubitemid 46871337)
292. Mansson-Broberg, A. et al. Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation. Biochem. Biophys. Res. Commun. 373, 355-359 (2008).
293. Niessen, K. et al. The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development. Blood 118, 1989-1997 (2011).
294. Stephen, L. J., Fawkes, A. L., Verhoeve, A., Lemke, G. & Brown, A. A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev. Biol. 302, 66-79 (2007). (Pubitemid 46096924)
295. Frieden, L. A. et al. Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev. Dyn. 239, 3226-3234 (2010).
296. Deroanne, C., Vouret-Craviari, V., Wang, B. & Pouyssegur, J. EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J. Cell Sci. 116, 1367-1376 (2003). (Pubitemid 36410674)
297. Okazaki, T. et al. Capillary defects and exaggerated inflammatory response in the airways of EphA2-deficient mice. Am. J. Pathol. 174, 2388-2399 (2009).
298. Davis, S. et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266, 816-819 (1994). (Pubitemid 24359293)
299. Conover, J. C. et al. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nature Neurosci. 3, 1091-1097 (2000).
300. Himanen, J. P. et al. Crystal structure of an Eph receptor-ephrin complex. Nature 414, 933-938 (2001).
301. Seiradake, E., Harlos, K., Sutton, G., Aricescu, A. R. & Jones, E. Y. An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly. Nature Struct. Mol. Biol. 17, 398-402 (2010).
302. Himanen, J. P. et al. Architecture of Eph receptor clusters. Proc. Natl Acad. Sci. USA 107, 10860-10865 (2010).
303. Peng, L., Oganesyan, V., Damschroder, M. M., Wu, H. & Dall'Acqua, W. F. Structural and Functional Characterization of an Agonistic Anti-Human EphA2 Monoclonal Antibody. J. Mol. Biol. 413, 390-405 (2011).
304. Zhao, X. et al. Vaccines targeting tumor blood vessel antigens promote CD8+ T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. J. Immunol. 188, 1782-1788 (2012).
305. Genet, G. et al. 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 (2012).