Home LiteratureArticle Details
PMID: 20179713 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review

Eph receptors and ephrins in cancer: bidirectional signalling and beyond.

Nature reviews. Cancer ·Vol. 10 ·No. 3 ·2010-03-00 ·Pages 165-80

Pasquale EB

Abstract

The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression. Eph gene mutations probably also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth, migration and invasion of cancer cells in culture as well as tumour growth, invasiveness, angiogenesis and metastasis in vivo. However, Eph signalling activities in cancer seem to be complex, and are characterized by puzzling dichotomies. Nevertheless, the Eph receptors are promising new therapeutic targets in cancer.

MeSH Terms
Animals Ephrins/metabolism Gene Expression Regulation, Neoplastic Humans Neoplasms/genetics,metabolism,pathology,physiopathology Receptors, Eph Family/genetics,metabolism Signal Transduction
Chemicals
Ephrins Receptors, Eph Family
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Pasquale Elena B
Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. [email protected]
References (226)
226 references, click to expand
  1. Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor.
    J Biol Chem. 2008 Oct 24;283(43):29473-84 PMID: 18708347
  2. Somatic mutations of the protein kinase gene family in human lung cancer.
    Cancer Res. 2005 Sep 1;65(17):7591-5 PMID: 16140923
  3. Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase.
    Mol Biol Cell. 2009 May;20(10):2572-81 PMID: 19321667
  4. Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin.
    Cancer Res. 2006 Jul 15;66(14):7050-8 PMID: 16849550
  5. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB.
    Cell. 2002 Oct 18;111(2):251-63 PMID: 12408869
  6. Receptor tyrosine kinase EphB4 is a survival factor in breast cancer.
    Am J Pathol. 2006 Jul;169(1):279-93 PMID: 16816380
  7. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice.
    Eur J Nucl Med Mol Imaging. 2007 Dec;34(12):2024-36 PMID: 17673999
  8. ZHX2 Interacts with Ephrin-B and regulates neural progenitor maintenance in the developing cerebral cortex.
    J Neurosci. 2009 Jun 10;29(23):7404-12 PMID: 19515908
  9. Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis.
    Oncogene. 2007 Jan 11;26(2):312-20 PMID: 16819509
  10. ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3.
    Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17305-10 PMID: 17954917
  11. Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines.
    PLoS One. 2008 Jul 23;3(7):e2780 PMID: 18648668
  12. Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer.
    Mod Pathol. 2006 Oct;19(10):1369-77 PMID: 16862074
  13. PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells.
    J Clin Invest. 2007 Jun;117(6):1527-37 PMID: 17510705
  14. ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers.
    Genomics. 1997 Mar 1;40(2):371-4 PMID: 9119409
  15. c-Rel is a transcriptional repressor of EPHB2 in colorectal cancer.
    J Pathol. 2009 Sep;219(1):103-13 PMID: 19621336
  16. Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling.
    EMBO J. 2006 Mar 22;25(6):1242-52 PMID: 16511561
  17. Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4).
    J Med Chem. 2009 Oct 22;52(20):6433-46 PMID: 19788238
  18. Ephrin-B2-induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion.
    J Biol Chem. 2008 Oct 24;283(43):28969-79 PMID: 18713744
  19. Patterns of somatic mutation in human cancer genomes.
    Nature. 2007 Mar 8;446(7132):153-8 PMID: 17344846
  20. Enhancement in specific CD8+ T cell recognition of EphA2+ tumors in vitro and in vivo after treatment with ligand agonists.
    J Immunol. 2008 Dec 1;181(11):7721-7 PMID: 19017961
  21. Molecular characterization and chromosomal localization of DRT (EPHT3): a developmentally regulated human protein-tyrosine kinase gene of the EPH family.
    Hum Mol Genet. 1995 Nov;4(11):2033-45 PMID: 8589679
  22. Structure and thermodynamic characterization of the EphB4/Ephrin-B2 antagonist peptide complex reveals the determinants for receptor specificity.
    Structure. 2006 Feb;14(2):321-30 PMID: 16472751
  23. EphB4 controls blood vascular morphogenesis during postnatal angiogenesis.
    EMBO J. 2006 Feb 8;25(3):628-41 PMID: 16424904
  24. Eph/ephrin signaling: networks.
    Genes Dev. 2008 Feb 15;22(4):416-29 PMID: 18281458
  25. Disease stage variation in CD4+ and CD8+ T-cell reactivity to the receptor tyrosine kinase EphA2 in patients with renal cell carcinoma.
    Cancer Res. 2003 Aug 1;63(15):4481-9 PMID: 12907621
  26. Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors.
    Neoplasia. 2003 Sep-Oct;5(5):445-56 PMID: 14670182
  27. Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis.
    Curr Biol. 2003 Sep 16;13(18):1571-82 PMID: 13678588
  28. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics.
    Curr Cancer Drug Targets. 2005 May;5(3):149-57 PMID: 15892616
  29. EphB-ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells.
    Nat Genet. 2007 Nov;39(11):1376-83 PMID: 17906625
  30. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647.
    Clin Cancer Res. 2007 Jun 15;13(12):3713-23 PMID: 17575237
  31. Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas.
    Oncogene. 2007 Jun 21;26(29):4243-52 PMID: 17260020
  32. Activation of the EGFR gene target EphA2 inhibits epidermal growth factor-induced cancer cell motility.
    Mol Cancer Res. 2007 Mar;5(3):283-93 PMID: 17374733
  33. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis.
    Cancer Res. 2004 Aug 15;64(16):5578-86 PMID: 15313894
  34. Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.
    BMC Cancer. 2009 Jul 16;9:237 PMID: 19607727
  35. Regulated cleavage of a contact-mediated axon repellent.
    Science. 2000 Aug 25;289(5483):1360-5 PMID: 10958785
  36. 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. 2008 May 1;18(9):2776-80 PMID: 18434142
  37. Role of ephrinB2 expression in endothelial cells during arteriogenesis: impact on smooth muscle cell migration and monocyte recruitment.
    Blood. 2008 Jul 1;112(1):73-81 PMID: 18445690
  38. Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors.
    J Biol Chem. 2008 Oct 24;283(43):29461-72 PMID: 18728010
  39. Novel splice variants derived from the receptor tyrosine kinase superfamily are potential therapeutics for rheumatoid arthritis.
    Arthritis Res Ther. 2008;10(4):R73 PMID: 18593464
  40. The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome.
    Br J Cancer. 2007 Apr 10;96(7):1083-91 PMID: 17353927
  41. Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis.
    J Cell Sci. 1998 Sep;111 ( Pt 18):2741-51 PMID: 9718367
  42. The soluble extracellular domain of EphB4 (sEphB4) antagonizes EphB4-EphrinB2 interaction, modulates angiogenesis, and inhibits tumor growth.
    Blood. 2006 Mar 15;107(6):2330-8 PMID: 16322467
  43. EPHA2 is associated with age-related cortical cataract in mice and humans.
    PLoS Genet. 2009 Jul;5(7):e1000584 PMID: 19649315
  44. Differential expression of EphA7 receptor tyrosine kinase in gastric carcinoma.
    Hum Pathol. 2007 Nov;38(11):1649-56 PMID: 17669470
  45. Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers.
    Clin Chem. 2004 Mar;50(3):490-9 PMID: 14726470
  46. Transcriptional silencing of EphB6 receptor tyrosine kinase in invasive breast carcinoma cells and detection of methylated promoter by methylation specific PCR.
    Biochem Biophys Res Commun. 2006 Feb 3;340(1):268-76 PMID: 16364251
  47. Ephrin expression and function in cancer.
    Future Oncol. 2010 Jan;6(1):165-76 PMID: 20021216
  48. The Eph family: a multitude of receptors that mediate cell recognition signals.
    Cell Tissue Res. 1997 Nov;290(2):217-26 PMID: 9321683
  49. The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors.
    Cell. 2008 Jun 13;133(6):963-77 PMID: 18555774
  50. Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains.
    Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):18866-71 PMID: 16365308
  51. Eph/ephrin signaling in epithelial development and homeostasis.
    Int J Biochem Cell Biol. 2009 Apr;41(4):762-70 PMID: 18761422
  52. Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo.
    World J Gastroenterol. 2009 Jun 14;15(22):2754-62 PMID: 19522026
  53. EphA2 as a target for ovarian cancer therapy.
    Expert Opin Ther Targets. 2005 Dec;9(6):1179-87 PMID: 16300469
  54. Humanized anti-EphB4 antibodies for the treatment of carcinomas and vasculogenesis-related diseases.
    Expert Opin Ther Pat. 2009 Jul;19(7):1035-7 PMID: 19552516
  55. Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis.
    Mol Cancer Res. 2009 Jul;7(7):1021-32 PMID: 19567782
  56. Detection of genetic alterations in advanced prostate cancer by comparative genomic hybridization.
    Cancer Genet Cytogenet. 2002 Aug;137(1):59-63 PMID: 12377415
  57. Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor.
    J Biol Chem. 2007 Jun 1;282(22):16155-63 PMID: 17428795
  58. EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma.
    J Natl Cancer Inst. 2009 Sep 2;101(17):1193-205 PMID: 19641174
  59. Beta2-chimaerin binds to EphA receptors and regulates cell migration.
    FEBS Lett. 2009 Apr 17;583(8):1237-42 PMID: 19306875
  60. EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures.
    Blood. 2009 Aug 20;114(8):1707-16 PMID: 19411631
  61. Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors.
    Cancer Res. 2005 Nov 15;65(22):10170-3 PMID: 16288001
  62. EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer.
    Cancer Res. 2004 Feb 1;64(3):781-8 PMID: 14871799
  63. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer.
    Cancer Res. 2005 Mar 1;65(5):1778-82 PMID: 15753374
  64. The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis.
    Cancer Res. 2009 Sep 15;69(18):7430-8 PMID: 19738063
  65. Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase. Role of Rho family small GTPases.
    J Biol Chem. 2005 Jan 14;280(2):923-32 PMID: 15536074
  66. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer.
    Br J Cancer. 2008 Oct 7;99(7):1074-82 PMID: 18797457
  67. Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation.
    J Cell Biol. 2009 May 4;185(3):551-64 PMID: 19414612
  68. MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3.
    J Biol Chem. 2008 Jun 6;283(23):15878-83 PMID: 18417479
  69. Fluid shear stress induces arterial differentiation of endothelial progenitor cells.
    J Appl Physiol (1985). 2009 Jan;106(1):203-11 PMID: 18988767
  70. Genomic structure and loss of heterozygosity of EPHB2 in colorectal cancer.
    Cancer Lett. 2001 Mar 10;164(1):97-104 PMID: 11166921
  71. Regeneration-enhancing effects of EphA4 blocking peptide following corticospinal tract injury in adult rat spinal cord.
    Eur J Neurosci. 2007 Nov;26(9):2496-505 PMID: 17970742
  72. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway.
    Nat Cell Biol. 2001 May;3(5):527-30 PMID: 11331884
  73. Inhibition of tumor growth and angiogenesis by soluble EphB4.
    Neoplasia. 2004 May-Jun;6(3):248-57 PMID: 15153337
  74. Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration.
    J Biol Chem. 2005 Aug 12;280(32):29355-63 PMID: 15955811
  75. EphA2 as a glioma-associated antigen: a novel target for glioma vaccines.
    Neoplasia. 2005 Aug;7(8):717-22 PMID: 16207473
  76. Identification of candidate predictive and surrogate molecular markers for dasatinib in prostate cancer: rationale for patient selection and efficacy monitoring.
    Genome Biol. 2007;8(11):R255 PMID: 18047674
  77. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.
    Nat Genet. 2009 Oct;41(10):1127-32 PMID: 19718025
  78. Hypoxia induces microRNA miR-210 in vitro and in vivo ephrin-A3 and neuronal pentraxin 1 are potentially regulated by miR-210.
    FEBS Lett. 2008 Jul 9;582(16):2397-401 PMID: 18539147
  79. EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma.
    Oncogene. 2004 Feb 19;23(7):1448-56 PMID: 14973554
  80. Ephrin-B2 overexpression enhances integrin-mediated ECM-attachment and migration of B16 melanoma cells.
    Int J Oncol. 2005 Nov;27(5):1197-206 PMID: 16211213
  81. Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival.
    Br J Cancer. 2009 Apr 7;100(7):1095-102 PMID: 19277044
  82. The consensus coding sequences of human breast and colorectal cancers.
    Science. 2006 Oct 13;314(5797):268-74 PMID: 16959974
  83. Tsc2-Rheb signaling regulates EphA-mediated axon guidance.
    Nat Neurosci. 2010 Feb;13(2):163-72 PMID: 20062052
  84. 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. 2000 Sep 1;60(17):4855-63 PMID: 10987298
  85. Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype.
    Cancer Res. 2009 Feb 1;69(3):836-44 PMID: 19176381
  86. Over-expression of EphB3 enhances cell-cell contacts and suppresses tumor growth in HT-29 human colon cancer cells.
    Carcinogenesis. 2009 Sep;30(9):1475-86 PMID: 19483190
  87. Overexpression confers an oncogenic potential upon the eph gene.
    Oncogene. 1990 Mar;5(3):445-7 PMID: 2314900
  88. Ephrin-A1 expression contributes to the malignant characteristics of {alpha}-fetoprotein producing hepatocellular carcinoma.
    Gut. 2005 Jun;54(6):843-51 PMID: 15888795
  89. Targeting the EphA4 receptor in the nervous system with biologically active peptides.
    Mol Cell Neurosci. 2003 Dec;24(4):1000-11 PMID: 14697664
  90. Bidirectional modulation of synaptic functions by Eph/ephrin signaling.
    Nat Neurosci. 2009 Jan;12(1):15-20 PMID: 19029886
  91. Heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhances EphA2+ tumor cell recognition by specific CD8+ T cells.
    Cancer Res. 2009 Sep 1;69(17):6995-7003 PMID: 19690146
  92. EphB4 expression and biological significance in prostate cancer.
    Cancer Res. 2005 Jun 1;65(11):4623-32 PMID: 15930280
  93. Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers.
    Carcinogenesis. 2007 Jun;28(6):1364-70 PMID: 17183069
  94. Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines.
    Cancer. 2007 Oct 1;110(7):1469-77 PMID: 17685394
  95. Somatic mutations affect key pathways in lung adenocarcinoma.
    Nature. 2008 Oct 23;455(7216):1069-75 PMID: 18948947
  96. A conditional feedback loop regulates Ras activity through EphA2.
    Cancer Cell. 2005 Aug;8(2):111-8 PMID: 16098464
  97. EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style.
    Cancer Res. 2009 Mar 1;69(5):2072-81 PMID: 19244130
  98. Tissue transglutaminase clusters soluble A-type ephrins into functionally active high molecular weight oligomers.
    Exp Cell Res. 2007 Dec 10;313(20):4170-9 PMID: 17707797
  99. A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo.
    Cancer Res. 2008 Nov 15;68(22):9367-74 PMID: 19010911
  100. Phosphorylation of ephrin-B1 via the interaction with claudin following cell-cell contact formation.
    EMBO J. 2005 Nov 2;24(21):3700-11 PMID: 16211011
  101. Loss of ephrin-A5 function disrupts lens fiber cell packing and leads to cataract.
    Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16620-5 PMID: 18948590
  102. EphrinA I-targeted nanoshells for photothermal ablation of prostate cancer cells.
    Int J Nanomedicine. 2008;3(3):351-8 PMID: 18990944
  103. Paradoxes of the EphB4 receptor in cancer.
    Cancer Res. 2007 May 1;67(9):3994-7 PMID: 17483308
  104. Structure-based tailoring of compound libraries for high-throughput screening: discovery of novel EphB4 kinase inhibitors.
    Proteins. 2008 Oct;73(1):11-8 PMID: 18384152
  105. A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor expressing tumor cells.
    Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3208-18 PMID: 18089715
  106. Genetic analysis identifies putative tumor suppressor sites at 2q35-q36.1 and 2q36.3-q37.1 involved in cervical cancer progression.
    Oncogene. 2003 May 29;22(22):3489-99 PMID: 12776201
  107. EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesis.
    Biochim Biophys Acta. 2009 Feb;1793(2):231-8 PMID: 18948148
  108. Dissecting the EphA3/Ephrin-A5 interactions using a novel functional mutagenesis screen.
    J Biol Chem. 2004 Mar 5;279(10):9522-31 PMID: 14660665
  109. Selective removal of ovarian cancer cells from human ascites fluid using magnetic nanoparticles.
    Nanomedicine. 2010 Jun;6(3):399-408 PMID: 19969103
  110. Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression.
    Exp Cell Res. 2006 Mar 10;312(5):642-50 PMID: 16330025
  111. The role of ephrins and Eph receptors in cancer.
    Cytokine Growth Factor Rev. 2004 Dec;15(6):419-33 PMID: 15561600
  112. Magnetic nanoparticle-peptide conjugates for in vitro and in vivo targeting and extraction of cancer cells.
    J Am Chem Soc. 2008 Aug 6;130(31):10258-62 PMID: 18611005
  113. Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation.
    J Biol Chem. 2007 Jan 26;282(4):2683-94 PMID: 17135240
  114. High EPHB2 mutation rate in gastric but not endometrial tumors with microsatellite instability.
    Oncogene. 2007 Jan 11;26(2):308-11 PMID: 16819508
  115. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism.
    J Cell Sci. 2008 Feb 1;121(Pt 3):358-68 PMID: 18198190
  116. Design and effective synthesis of novel templates, 3,7-diphenyl-4-amino-thieno and furo-[3,2-c]pyridines as protein kinase inhibitors and in vitro evaluation targeting angiogenetic kinases.
    Bioorg Med Chem Lett. 2007 Jan 1;17(1):250-4 PMID: 17027260
  117. A novel mechanism for p53 to regulate its target gene ECK in signaling apoptosis.
    Mol Cancer Res. 2006 Oct;4(10):769-78 PMID: 17050670
  118. Constitutive activation of the Raf-MAPK pathway causes negative feedback inhibition of Ras-PI3K-AKT and cellular arrest through the EphA2 receptor.
    Oncogene. 2008 May 1;27(20):2934-40 PMID: 18059341
  119. In human leukemia cells ephrin-B-induced invasive activity is supported by Lck and is associated with reassembling of lipid raft signaling complexes.
    Mol Cancer Res. 2008 Feb;6(2):291-305 PMID: 18314490
  120. The role of Ephs, Ephrins, and growth factors in Kaposi sarcoma and implications of EphrinB2 blockade.
    Blood. 2009 Jan 1;113(1):254-63 PMID: 18836096
  121. A quantitative analysis of kinase inhibitor selectivity.
    Nat Biotechnol. 2008 Jan;26(1):127-32 PMID: 18183025
  122. Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O.
    Nat Neurosci. 2006 Jun;9(6):761-9 PMID: 16680165
  123. Dual targeting of EphA2 and FAK in ovarian carcinoma.
    Cancer Biol Ther. 2009 Jun;8(11):1027-34 PMID: 19395869
  124. EphA kinase activation regulates HGF-induced epithelial branching morphogenesis.
    J Cell Biol. 2003 Sep 29;162(7):1281-92 PMID: 14517207
  125. The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion.
    Int J Cancer. 2010 Mar 1;126(5):1155-65 PMID: 19728339
  126. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway.
    Nat Cell Biol. 2006 Aug;8(8):815-25 PMID: 16862147
  127. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis.
    Science. 1995 Apr 28;268(5210):567-9 PMID: 7536959
  128. EphB receptor-binding peptides identified by phage display enable design of an antagonist with ephrin-like affinity.
    J Biol Chem. 2005 Apr 29;280(17):17301-11 PMID: 15722342
  129. Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry.
    Cancer Biol Ther. 2008 May;7(5):758-66 PMID: 18376140
  130. Aberrant methylation of EphA7 in human prostate cancer and its relation to clinicopathologic features.
    Int J Cancer. 2009 Jan 1;124(1):88-94 PMID: 18821581
  131. EPH receptors in cancer.
    Histol Histopathol. 2008 Aug;23(8):1011-23 PMID: 18498077
  132. Anti-EphA2 antibodies decrease EphA2 protein levels in murine CT26 colorectal and human MDA-231 breast tumors but do not inhibit tumor growth.
    Neoplasia. 2006 Jan;8(1):18-30 PMID: 16533422
  133. Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor.
    Biochem J. 2009 Aug 27;422(3):433-42 PMID: 19552627
  134. Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines.
    Bioorg Med Chem Lett. 2008 Nov 1;18(21):5717-21 PMID: 18851911
  135. EphB receptor activity suppresses colorectal cancer progression.
    Nature. 2005 Jun 23;435(7045):1126-30 PMID: 15973414
  136. An ephrin mimetic peptide that selectively targets the EphA2 receptor.
    J Biol Chem. 2002 Dec 6;277(49):46974-9 PMID: 12351647
  137. Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior.
    Cancer Res. 2002 May 15;62(10):2840-7 PMID: 12019162
  138. Phosphorylation of ephrin-B1 regulates dissemination of gastric scirrhous carcinoma.
    Am J Pathol. 2007 Jul;171(1):68-78 PMID: 17591954
  139. Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.
    Science. 2009 Oct 9;326(5950):294-8 PMID: 19815777
  140. EphA2 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes.
    Cancer Res. 2003 Dec 1;63(23):8476-80 PMID: 14679012
  141. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1.
    J Biol Chem. 2008 Jul 4;283(27):18926-36 PMID: 18434321
  142. Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis.
    Oncogene. 2001 Oct 4;20(45):6503-15 PMID: 11641774
  143. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors.
    Cancer Cell. 2005 Oct;8(4):299-309 PMID: 16226705
  144. Regulation of angiogenesis by Eph-ephrin interactions.
    Trends Cardiovasc Med. 2007 Jul;17(5):145-51 PMID: 17574121
  145. Differential EphA2 epitope display on normal versus malignant cells.
    Cancer Res. 2003 Nov 15;63(22):7907-12 PMID: 14633720
  146. EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion.
    Am J Pathol. 2005 Aug;167(2):565-76 PMID: 16049340
  147. Eph receptor signalling casts a wide net on cell behaviour.
    Nat Rev Mol Cell Biol. 2005 Jun;6(6):462-75 PMID: 15928710
  148. The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells.
    J Cell Sci. 2007 Jul 1;120(Pt 13):2179-89 PMID: 17567680
  149. Capillary defects and exaggerated inflammatory response in the airways of EphA2-deficient mice.
    Am J Pathol. 2009 Jun;174(6):2388-99 PMID: 19443703
  150. Chromosomal abnormalities in cancer.
    N Engl J Med. 2008 Aug 14;359(7):722-34 PMID: 18703475
  151. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization.
    Oncogene. 2000 Dec 7;19(52):6043-52 PMID: 11146556
  152. Downregulation of EphA7 by hypermethylation in colorectal cancer.
    Oncogene. 2005 Aug 25;24(36):5637-47 PMID: 16007213
  153. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor.
    Oncogene. 2008 Dec 11;27(58):7260-73 PMID: 18794797
  154. MASPIT: three-hybrid trap for quantitative proteome fingerprinting of small molecule-protein interactions in mammalian cells.
    Chem Biol. 2006 Jul;13(7):711-22 PMID: 16873019
  155. Efficacy and antivascular effects of EphA2 reduction with an agonistic antibody in ovarian cancer.
    J Natl Cancer Inst. 2006 Nov 1;98(21):1558-70 PMID: 17077358
  156. EPHB4 and survival of colorectal cancer patients.
    Cancer Res. 2006 Sep 15;66(18):8943-8 PMID: 16982731
  157. Discovery and structural analysis of Eph receptor tyrosine kinase inhibitors.
    Bioorg Med Chem Lett. 2009 Aug 1;19(15):4467-70 PMID: 19553108
  158. Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors.
    Bioorg Med Chem Lett. 2009 Nov 1;19(21):6122-6 PMID: 19783434
  159. Identification and classification of p53-regulated genes.
    Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14517-22 PMID: 10588737
  160. EphA2 engages Git1 to suppress Arf6 activity modulating epithelial cell-cell contacts.
    Mol Biol Cell. 2009 Apr;20(7):1949-59 PMID: 19193766
  161. Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo.
    Oncogene. 2002 Oct 10;21(46):7011-26 PMID: 12370823
  162. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy.
    Cancer Res. 2010 Jan 1;70(1):299-308 PMID: 20028874
  163. The association between elevated EphB4 expression, smoking status, and advanced-stage disease in patients with head and neck squamous cell carcinoma.
    Arch Otolaryngol Head Neck Surg. 2006 Oct;132(10):1053-9 PMID: 17043250
  164. Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression.
    Cancer Res. 2001 Feb 15;61(4):1320-6 PMID: 11245428
  165. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling.
    J Clin Invest. 2008 Jan;118(1):64-78 PMID: 18079969
  166. Vascular remodeling marks tumors that recur during chronic suppression of angiogenesis.
    Mol Cancer Res. 2004 Jan;2(1):36-42 PMID: 14757844
  167. Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells.
    Blood. 1999 Oct 1;94(7):2477-86 PMID: 10498621
  168. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery.
    Cancer Res. 2005 Aug 1;65(15):6910-8 PMID: 16061675
  169. A novel putative tyrosine kinase receptor encoded by the eph gene.
    Science. 1987 Dec 18;238(4834):1717-20 PMID: 2825356
  170. An efficient rapid system for profiling the cellular activities of molecular libraries.
    Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3153-8 PMID: 16492761
  171. Ephrin A5 expression promotes invasion and transformation of murine fibroblasts.
    Biochem Biophys Res Commun. 2006 Nov 24;350(3):623-8 PMID: 17022942
  172. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection.
    Cancer Res. 2007 Mar 1;67(5):2226-38 PMID: 17332353
  173. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression.
    Cell. 2009 Nov 13;139(4):679-92 PMID: 19914164
  174. EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility.
    J Cell Sci. 2009 Jan 15;122(Pt 2):243-55 PMID: 19118217
  175. EphA4 as an effector of Twist1 in the guidance of osteogenic precursor cells during calvarial bone growth and in craniosynostosis.
    Development. 2009 Mar;136(5):855-64 PMID: 19201948
  176. The EphA2 receptor and ephrinA1 ligand in solid tumors: function and therapeutic targeting.
    Mol Cancer Res. 2008 Dec;6(12):1795-806 PMID: 19074825
  177. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis.
    Oncogene. 2005 Nov 24;24(53):7859-68 PMID: 16103880
  178. Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates SRC invasive activity in advanced colon carcinoma cells.
    Cancer Res. 2009 Mar 15;69(6):2279-86 PMID: 19276381
  179. EphA2 overexpression causes tumorigenesis of mammary epithelial cells.
    Cancer Res. 2001 Mar 1;61(5):2301-6 PMID: 11280802
  180. EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival.
    Oncogene. 2006 Feb 2;25(5):769-80 PMID: 16205642
  181. VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry.
    Cancer Biol Ther. 2006 Feb;5(2):228-33 PMID: 16481735
  182. High-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity.
    Genes Chromosomes Cancer. 2004 Nov;41(3):250-6 PMID: 15334548
  183. EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line.
    Mol Cancer Ther. 2008 Sep;7(9):2768-78 PMID: 18790757
  184. EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel.
    Dev Biol. 2009 Mar 15;327(2):313-26 PMID: 19135438
  185. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression.
    J Biol Chem. 2004 Apr 2;279(14):13383-92 PMID: 14729671
  186. Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist.
    Cancer Res. 2004 Feb 1;64(3):910-9 PMID: 14871820
  187. Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly.
    Cell. 2006 Jan 13;124(1):161-73 PMID: 16413489
  188. Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice.
    Cancer Res. 2006 Nov 1;66(21):10315-24 PMID: 17079451
  189. Endothelial EphA receptor stimulation increases lung vascular permeability.
    Am J Physiol Lung Cell Mol Physiol. 2008 Sep;295(3):L431-9 PMID: 18599503
  190. Meltrin beta/ADAM19 interacting with EphA4 in developing neural cells participates in formation of the neuromuscular junction.
    PLoS One. 2008 Oct 02;3(10):e3322 PMID: 18830404
  191. B61 is a ligand for the ECK receptor protein-tyrosine kinase.
    Nature. 1994 Apr 7;368(6471):558-60 PMID: 8139691
  192. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer.
    Nat Genet. 2004 Sep;36(9):979-83 PMID: 15300251
  193. EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor.
    Oncogene. 2009 Apr 16;28(15):1759-68 PMID: 19270726
  194. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase.
    Cell Growth Differ. 1999 Sep;10(9):629-38 PMID: 10511313
  195. Ephrin-B3 ligand promotes glioma invasion through activation of Rac1.
    Cancer Res. 2006 Sep 1;66(17):8492-500 PMID: 16951161
  196. Expression of Eph receptors and ephrins is differentially regulated by E-cadherin.
    J Cell Sci. 2000 May;113 ( Pt 10):1793-802 PMID: 10769210
  197. Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion.
    J Cell Sci. 2006 Apr 1;119(Pt 7):1244-54 PMID: 16522685
  198. A role for C. elegans Eph RTK signaling in PTEN regulation.
    Dev Cell. 2009 Oct;17(4):459-69 PMID: 19853560
  199. Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning.
    Nat Neurosci. 2009 Mar;12(3):268-76 PMID: 19182796
  200. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt.
    Cancer Cell. 2009 Jul 7;16(1):9-20 PMID: 19573808
  201. 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. 2008 Aug;99(8):1656-62 PMID: 18754880
  202. p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping.
    Neuron. 2008 Sep 11;59(5):746-58 PMID: 18786358
  203. Selective targeting and potent control of tumor growth using an EphA2/CD3-Bispecific single-chain antibody construct.
    Cancer Res. 2007 Apr 15;67(8):3927-35 PMID: 17440108
  204. Antibody-dependent cell-mediated cytotoxicity effector-enhanced EphA2 agonist monoclonal antibody demonstrates potent activity against human tumors.
    Neoplasia. 2009 Jun;11(6):509-17, 2 p following 517 PMID: 19484140
  205. The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner.
    Mol Cell Biol. 2001 Jul;21(14):4579-97 PMID: 11416136
  206. Cell signaling in space and time: where proteins come together and when they're apart.
    Science. 2009 Nov 27;326(5957):1220-4 PMID: 19965465
  207. Eph receptor-ephrin bidirectional signals that target Ras and Rho proteins.
    Cell Signal. 2004 Jun;16(6):655-66 PMID: 15093606
  208. Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis.
    Mol Cancer Res. 2002 Nov;1(1):2-11 PMID: 12496364
  209. Multiple in vivo tyrosine phosphorylation sites in EphB receptors.
    Biochemistry. 1999 Oct 26;38(43):14396-408 PMID: 10572014
  210. Eph-ephrin bidirectional signaling in physiology and disease.
    Cell. 2008 Apr 4;133(1):38-52 PMID: 18394988
  211. Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway.
    J Cell Biol. 2008 Dec 1;183(5):933-47 PMID: 19047466
  212. Regulation of the EphA2 kinase by the low molecular weight tyrosine phosphatase induces transformation.
    J Biol Chem. 2002 Oct 18;277(42):39274-9 PMID: 12167657
  213. Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis.
    Mol Cell Biol. 2006 Jul;26(13):4830-42 PMID: 16782872
  214. Germline EPHB2 receptor variants in familial colorectal cancer.
    PLoS One. 2008 Aug 06;3(8):e2885 PMID: 18682749
  215. Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth.
    Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5583-8 PMID: 15067119
  216. Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells.
    Blood. 2008 Aug 1;112(3):721-32 PMID: 18385452
  217. Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells.
    Science. 2009 Dec 11;326(5959):1502-9 PMID: 20007894
  218. Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines.
    Cancer Res. 2007 Dec 1;67(23):11368-76 PMID: 18056464
  219. Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents.
    Cancer Res. 2005 Aug 1;65(15):6745-54 PMID: 16061656
  220. Three-dimensional structure of the EphB2 receptor in complex with an antagonistic peptide reveals a novel mode of inhibition.
    J Biol Chem. 2007 Dec 14;282(50):36505-13 PMID: 17897949
  221. EphrinB1 controls cell-cell junctions through the Par polarity complex.
    Nat Cell Biol. 2008 Aug;10(8):979-86 PMID: 18604196
  222. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression.
    Cancer Res. 2009 May 1;69(9):3736-45 PMID: 19366806
  223. Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1.
    Cancer Gene Ther. 2004 Nov;11(11):757-66 PMID: 15359289
  224. The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization.
    J Biol Chem. 2006 Oct 27;281(43):32574-86 PMID: 16950769
  225. Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes.
    J Cell Sci. 2008 Nov 15;121(Pt 22):3842-50 PMID: 18957513
  226. Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling.
    J Cell Biol. 2008 Nov 17;183(4):711-23 PMID: 19001122
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc2806
Email
[email protected]
Published
2010-03-00
Pages
165-80
Language
English
Region
England
NLM ID
101124168
PMCID
PMC2921274
Subset
IM
Grants
NCI NIH HHS · P01 CA138390 · United States
NCI NIH HHS · P01 CA138390-01A1 · United States
NINDS NIH HHS · R21 NS067502-01 · United States
NICHD NIH HHS · P01 HD025938-19 · United States
NCI NIH HHS · P01 CA102583-05 · United States
NCI NIH HHS · R01 CA116099 · United States
NCI NIH HHS · R01 CA116099-05 · United States
NICHD NIH HHS · P01 HD025938 · United States
NINDS NIH HHS · R21 NS067502 · United States
NCI NIH HHS · P01 CA102583 · United States
External Links
PubMed source DOI: 10.1038/nrc2806 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2