Research progress on the biological functions and related diseases mediated by the Eph/Ephrin signal transduction pathways
Chang Hongmin1, Zhu Guoqiang2, Li Chuanbao2
1College of Clinical Medicine, Jining Medical University, Jining 272013, China; 2Department of Ophthalmology, the Affiliated Hospital of Jining Medical University, Jining 272029, China
Abstract:Erythropoietin-producing hepatocyte (Eph) receptor is the largest receptors among the known receptor tyrosine kinase (RTKs) family. The Eph receptor plays an important role in human ontogeny and various disease development. On the one hand, the interaction between the Eph receptor and its membrane binding ligand (Ephrin) mediates a range of physiological and pathological processes spanning from embryonic development to adulthood. On the other hand, the Eph receptor can contribute to infection and immunity by binding to pathogen-related model molecules, mediating the occurrence and development of associated diseases. This article reviews the latest research progress on the biological functions and related diseases mediated by the Eph/Ephrin signal transduction pathways in recent years and summarizes the role of the Eph receptor and Ephrin in the nervous system, angiogenesis, tumor development, infection, and immunity.
常红敏 朱国强 李传宝. Eph/Ephrin信号转导途径介导的生物学功能及其相关
疾病的研究进展[J]. 中华诊断学电子杂志, 2024, 12(1): 64-68.
Chang Hongmin1, Zhu Guoqiang2, Li Chuanbao2. Research progress on the biological functions and related diseases mediated by the Eph/Ephrin signal transduction pathways. zhzdx, 2024, 12(1): 64-68.
[1]Vreeken D,Zhang H,van Zonneveld AJ,et al.Ephs and Ephrins in adult endothelial biology[J].Int J Mol Sci,2020,21(16):5623.DOI:10.3390/ijms21165623.
[2]de Boer E,van Gils JM,van Gils MJ.Ephrin-Eph signaling usage by a variety of viruses[J].Pharmacol Res,2020(159):105038.DOI:10.1016/j.phrs.2020.105038.
[3]Adu-Gyamfi EA,Czika A,Liu TH,et al.Ephrin and Eph receptor signaling in female reproductive physiology and pathology[J].Biol Reprod,2021,104(1):71-82.DOI:10.1093/biolre/ioaa171.
[4]Sahoo AR,Buck M.Structural and functional insights into the transmembrane domain association of Eph receptors[J].Int J Mol Sci,2021,22(16):8593.DOI:10.3390/ijms22168593.
[5]刘正,邵子玮,袁文华,等.Eph/ephrin信号通路与神经干细胞的增殖和分化[J].中国组织工程研究,2019,23(13):2101-2106.DOI:10.3969/j.issn.2095-4344.1654.
[6]Pasquale EB.Eph receptors and ephrins in cancer:bidirectional signalling and beyond[J].Nat Rev Cancer,2010,10(3):165-180.DOI:10.1038/nrc2806.
[7]Darling TK,Lamb TJ.Emerging roles for eph receptors and ephrin ligands in immunity [J].Front Immunol,2019(10):1473.DOI:10.3389/fimmu.2019.01473.
[8]Kania A,Klein R.Mechanisms of ephrin-Eph signalling in development,physiology and disease[J].Nat Rev Mol Cell Biol,2016,17(4):240-256.DOI:10.1038/nrm.2015.16.
[9]Wu B,Rockel JS,Lagares D,et al.Ephrins and eph receptor signaling in tissue repair and fibrosis [J].Curr Rheumatol Rep,2019,21(6):23.DOI:10.1007/s11926-019-0825-x.
[10]Liang LY,Patel O,Janes PW,et al.Eph receptor signalling:from catalytic to non-catalytic functions[J].Oncogene,2019,38(39):6567-6584.DOI:10.1038/s41388-019-0931-2.
[11]Cayuso J,Dzementsei A,Fischer JC,et al.Ephrinb1/Ephb3b coordinate bidirectional epithelial-mesenchymal interactions controlling liver morphogenesis and laterality[J].Dev Cell,2016,39(3):316-328.DOI:10.1016/j.devcel.2016.10.009.
[12]Gong J,Krner R,Gaitanos L,et al.Exosomes mediate cell contact-independent ephrin-Eph signaling during axon guidance[J].J Cell Biol,2016,214(1):35-44.DOI:10.1083/jcb.201601085.
[13]Buckens OJ,El Hassouni B,Giovannetti E,et al.The role of Eph receptors in cancer and how to target them:novel approaches in cancer treatment[J].Expert Opin Investig Drugs,2020,29(6):567-582.DOI:10.1080/13543784.2020.1762566.
[14]Nikas I,Ryu HS,Theocharis S.Viewing the Eph receptors with a focus on breast cancer heterogeneity[J].Cancer Lett,2018(434):160-171.DOI:10.1016/j.canlet.2018.07.030.
[15]Cramer KS,Miko IJ.Eph-ephrin signaling in nervous system development[J].F1000Res,2016(5):F1000 Faculty Rev-413 [pii].DOI:10.12688/f1000research.7417.1.
[16]Egea J,Klein R.Bidirectional Eph-ephrin signaling during axon guidance[J].Trends Cell Biol,2007,17(5):230-238.DOI:10.1016/j.tcb.2007.03.004.
[17]Bochenek ML,Dickinson S,Astin JW,et al.Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding[J].J Cell Sci,2010,123(Pt 8):1235-1246.DOI:10.1242/jcs.061903.
[18]Elorriaga V, Pierani A, Causeret F. Cajal-retzius cells:recent advances in identity and function[J].Curr Opin Neurobiol,2023(79):102686.DOI:10.1016/j.conb.2023.102686.
[19]Niethamer TK, Bush JO. Getting direction(s): the Eph/ephrin signaling system in cell positioning[J].Dev Biol,2019,447(1):42-57.DOI:10.1016/j.ydbio.2018.01.012.
[20]Wan Y,Yang JS,Xu LC,et al.Roles of Eph/ephrin bidirectional signaling during injury and recovery of the central nervous system[J].Neural Regen Res,2018,13(8):1313-1321.DOI:10.4103/1673-5374.235217.
[21]Yang JS,Wei HX,Chen PP,et al.Roles of Eph/ephrin bidirectional signaling in central nervous system injury and recovery[J].Exp Ther Med,2018,15(3):2219-2227.DOI:10.3892/etm.2018.5702.
[22]Yang J,Luo X,Huang X,et al.Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia[J].J Neurochem,2014,131(3):383-394.DOI:10.1111/jnc.12819.
[23]Kaczmarek R,Gajdzis P,Gajdzis M.Eph receptors and ephrins in retinal diseases [J].Int J Mol Sci,2021,22(12):6207.DOI:10.3390/ijms22126207.
[24]Chen Y,Zhang H,Zhang Y.Targeting receptor tyrosine kinase EphB4 in cancer therapy[J].Semin Cancer Biol,2019(56):37-46.DOI:10.1016/j.semcancer.2017.10.002.
[25]Piffko A,Uhl C,Vajkoczy P,et al.EphrinB2-EphB4 signaling in neurooncological disease[J].Int J Mol Sci,2022,23(3):1679.DOI:10.3390/ijms23031679.
[26]Coucha M,Barrett AC,Bailey J,et al.Increased Ephrin-B2 expression in pericytes contributes to retinal vascular death in rodents[J].Vascul Pharmacol,2020(131):106761.DOI:10.1016/j.vph.2020.106761.
[27]Zhou X,Tu P,Chen X,et al.Eph receptors:actors in tumor microenvironment [J].Crit Rev Oncog,2017,22(5/6):499-505.DOI:10.1615/CritRevOncog.2017020557.
[28]Nakayama A,Nakayama M,Turner CJ,et al.Ephrin-B2 controls PDGFRβ internalization and signaling[J].Genes Dev,2013,27(23):2576-2589.DOI:10.1101/gad.224089.113.
[29]Du MR,Yan L,Li NS,et al.Asymmetric dimethylarginine contributes to retinal neovascularization of diabetic retinopathy through EphrinB2 pathway[J].Vascul Pharmacol,2018(108):46-56.DOI:10.1016/j.vph.2018.05.004.
[30]Li Y, Chen D, Sun L, et al. Induced expression of VEGFC,ANGPT,and EFNB2 and their receptors characterizes neovascularization in proliferative diabetic retinopathy[J].Invest Ophthalmol Vis Sci,2019,60(13):4084-4096.DOI:10.1167/iovs.19-26767.
[31]Kaczmarek R,Zimmer K,Gajdzis P,et al.The role of eph receptors and ephrins in corneal physiology and diseases[J].Int J Mol Sci,2021,22(9):4567.DOI:10.3390/ijms22094567.
[32]Saito H,Oikawa M,Kouketsu A,et al.Immunohistochemical assessment of Eph/ephrin expression in oral squamous cell carcinoma and precursor lesions[J].Odontology,2020,108(2):166-173.DOI:10.1007/s10266-019-00466-y.
[33]Anderton M,van der Meulen E,Blumenthal MJ,et al.The role of the Eph receptor family in tumorigenesis[J].Cancers (Basel),2021,13(2):206.DOI:10.3390/cancers13020206.
[34]Leung HW,Leung C,Lau EY,et al.EPHB2 activates β-Catenin to Enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma[J].Cancer Res,2021,81(12):3229-3240.DOI:10.1158/0008-5472.CAN-21-0184.
[35]Wijeratne DT,Rodger J,Wood FM,et al.The role of Eph receptors and Ephrins in the skin[J].Int J Dermatol,2016,55(1):3-10.DOI:10.1111/ijd.12968.
[36]张飞,牛瑞芳.EphA2在乳腺癌治疗耐药中作用的研究进展[J].中国肿瘤临床,2021,48(15):792-796.DOI:10.12354/j.issn.1000-8179.2021.20211104.
[37]London M,Gallo E.The EphA2 and cancer connection:potential for immune-based interventions[J].Mol Biol Rep,2020,47(10):8037-8048.DOI:10.1007/s11033-020-05767-y.
[38]Markosyan N, Li J, Sun YH, et al. Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2)[J].J Clin Invest,2019,129(9):3594-3609.DOI:10.1172/JCI127755.
[39]Lau A,Le N,Nguyen C,et al.Signals transduced by Eph receptors and ephrin ligands converge on MAP kinase and AKT pathways in human cancers[J].Cell Signal,2023(104):110579.DOI:10.1016/j.cellsig.2022.110579.
[40]Zhao Y,Cai C,Zhang M,et al.Ephrin-A2 promotes prostate cancer metastasis by enhancing angiogenesis and promoting EMT[J].J Cancer Res Clin Oncol,2021,147(7):2013-2023.DOI:10.1007/s00432-021-03618-2.
[41]Lv XY,Wang J,Huang F,et al.EphA3 contributes to tumor growth and angiogenesis in human gastric cancer cells[J].Oncol Rep,2018,40(4):2408-2416.DOI:10.3892/or.2018.6586.
[42]Ieguchi K,Maru Y.Roles of EphA1/A2 and ephrin-A1 in cancer[J].Cancer Sci,2019,110(3):841-848.DOI:10.1111/cas.13942.
[43]Janes PW,Vail ME,Gan HK, et al. Antibody targeting of Eph receptors in cancer[J].Pharmaceuticals (Basel),2020,13(5):88.DOI:10.3390/ph13050088.
[44]Brantley-Sieders DM,Fang WB,Hicks DJ,et al.Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression[J].FASEB J,2005,19(13):1884-1886.DOI:10.1096/fj.05-4038fje.
[45]秦承东,任正刚,汤钊猷.缺氧微环境在肿瘤进展中的作用[J].肿瘤,2016,36(1):96-102.DOI:10.3781/j.issn.1000-7431.2016.55.563.
[46]To C,Farnsworth RH,Vail ME,et al.Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth[J].PLoS One,2014,9(11):e112106.DOI:10.1371/journal.pone.0112106.
[47]黄波.肿瘤微环境中免疫与炎症的调节[J].中国肿瘤生物治疗杂志,2012,19(2):111-115.DOI:10.3872/j.issn.1007-385X.2012.02.001.
[48]Ivanov AI, Romanovsky AA. Putative dual role of ephrin-Eph receptor interactions in inflammation[J].IUBMB Life,2006,58(7):389-394.DOI:10.1080/15216540600756004.
[49]Verma A,Gaffen SL,Swidergall M.Innate immunity to mucosal candida infections[J].J Fungi (Basel),2017,3(4):60.DOI:10.3390/jof3040060.
[50]Swidergall M,Solis NV,Wang Z,et al.Epha2 is a neutrophil receptor for candida albicans that stimulates antifungal activity during oropharyngeal infection [J].Cell Rep,2019,28(2):423-433.e5.DOI:10.1016/j.celrep.2019.06.020.
[51]Kottom TJ, Schaefbauer K, Carmona EM, et al. Epha2 is a lung epithelial cell receptor for pneumocystis β-glucans [J].J Infect Dis,2022,225(3):525-530.DOI:10.1093/infdis/jiab384.