Eph Receptors and Ephrins in Cancer: Bidirectional Signalling and Beyond

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2010 Feb 25

PMID 20179713

Citations 665

Authors

Elena B Pasquale

Affiliations

Soon will be listed here.

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.

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References

Qin H, Shi J, Noberini R, Pasquale E, Song J . 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; 283(43):29473-84. PMC: 2662028. DOI: 10.1074/jbc.M804114200. View

Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G . Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005; 65(17):7591-5. DOI: 10.1158/0008-5472.CAN-05-1855. View

Vaught D, Chen J, Brantley-Sieders D . Regulation of mammary gland branching morphogenesis by EphA2 receptor tyrosine kinase. Mol Biol Cell. 2009; 20(10):2572-81. PMC: 2682598. DOI: 10.1091/mbc.e08-04-0378. View

Guo H, Miao H, Gerber L, Singh J, Denning M, Gilliam A . Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res. 2006; 66(14):7050-8. DOI: 10.1158/0008-5472.CAN-06-0004. View

Batlle E, Henderson J, Beghtel H, van den Born M, Sancho E, Huls G . Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell. 2002; 111(2):251-63. DOI: 10.1016/s0092-8674(02)01015-2. View

Kumar S, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley E . Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol. 2006; 169(1):279-93. PMC: 1698769. DOI: 10.2353/ajpath.2006.050889. View

Cai W, Ebrahimnejad A, Chen K, Cao Q, Li Z, Tice D . Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging. 2007; 34(12):2024-36. DOI: 10.1007/s00259-007-0503-5. View

Wu C, Qiu R, Wang J, Zhang H, Murai K, Lu Q . ZHX2 Interacts with Ephrin-B and regulates neural progenitor maintenance in the developing cerebral cortex. J Neurosci. 2009; 29(23):7404-12. PMC: 2759685. DOI: 10.1523/JNEUROSCI.5841-08.2009. View

Laiho P, Kokko A, Vanharanta S, Salovaara R, Sammalkorpi H, Jarvinen H . Serrated carcinomas form a subclass of colorectal cancer with distinct molecular basis. Oncogene. 2006; 26(2):312-20. DOI: 10.1038/sj.onc.1209778. View

10.

Bong Y, Lee H, Carim-Todd L, Mood K, Nishanian T, Tessarollo L . ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3. Proc Natl Acad Sci U S A. 2007; 104(44):17305-10. PMC: 2077252. DOI: 10.1073/pnas.0702337104. View

11.

Winter J, Roepcke S, Krause S, Muller E, Otto A, Vingron M . Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines. PLoS One. 2008; 3(7):e2780. PMC: 2474680. DOI: 10.1371/journal.pone.0002780. View

12.

Hafner C, Becker B, Landthaler M, Vogt T . Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer. Mod Pathol. 2006; 19(10):1369-77. DOI: 10.1038/modpathol.3800660. View

13.

Foubert P, Silvestre J, Souttou B, Barateau V, Martin C, Ebrahimian T . PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells. J Clin Invest. 2007; 117(6):1527-37. PMC: 1866248. DOI: 10.1172/JCI28338. View

14.

Sulman E, Tang X, Allen C, Biegel J, Pleasure D, Brodeur G . ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers. Genomics. 1997; 40(2):371-4. DOI: 10.1006/geno.1996.4569. View

15.

Fu T, Li P, Wang H, He Y, Luo D, Zhang A . c-Rel is a transcriptional repressor of EPHB2 in colorectal cancer. J Pathol. 2009; 219(1):103-13. DOI: 10.1002/path.2590. View

16.

Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G . Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 2006; 25(6):1242-52. PMC: 1422162. DOI: 10.1038/sj.emboj.7601031. View

17.

Lafleur K, Huang D, Zhou T, Caflisch A, Nevado C . Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). J Med Chem. 2009; 52(20):6433-46. DOI: 10.1021/jm9009444. View

18.

Lin K, Sloniowski S, Ethell D, Ethell I . Ephrin-B2-induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion. J Biol Chem. 2008; 283(43):28969-79. PMC: 2570862. DOI: 10.1074/jbc.M804401200. View

19.

Greenman C, Stephens P, Smith R, Dalgliesh G, Hunter C, Bignell G . Patterns of somatic mutation in human cancer genomes. Nature. 2007; 446(7132):153-8. PMC: 2712719. DOI: 10.1038/nature05610. View

20.

Wesa A, Herrem C, Mandic M, Taylor J, Vasquez C, Kawabe M . Enhancement in specific CD8+ T cell recognition of EphA2+ tumors in vitro and in vivo after treatment with ligand agonists. J Immunol. 2008; 181(11):7721-7. PMC: 3427921. DOI: 10.4049/jimmunol.181.11.7721. View