EPH receptor A2 explained

EPH receptor A2 (ephrin type-A receptor 2) is a protein that in humans is encoded by the EPHA2 gene.^[1]

Function

This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into two groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands.^[2]

Clinical significance

It may be implicated in BRAF mutated melanomas becoming resistant to BRAF-inhibitors and MEK inhibitors.^[3] It is also the receptor by which Kaposi's sarcoma-associated herpesvirus (KSHV) enters host cells; small molecule inhibitors of EphA2 have shown some ability to block KSHV entry into human cells.^[4]

Interactions

EPH receptor A2 has been shown to interact with:

• Ephrin A1^[5]
• ACP1^[6]
• Grb2,^[7]
• PIK3R1,^[8] and
• SHC1.^[7]

It was also shown that doxazosin is a small molecule agonist of EPH receptor A2.^[9]

See also

• Vasculogenic mimicry

Further reading

• Flanagan JG, Vanderhaeghen P . 1278600 . The ephrins and Eph receptors in neural development . Annu. Rev. Neurosci. . 21 . 309–45 . 1998 . 9530499 . 10.1146/annurev.neuro.21.1.309 .
• Zhou R . The Eph family receptors and ligands . Pharmacol. Ther. . 77 . 3 . 151–81 . 1998 . 9576626 . 10.1016/S0163-7258(97)00112-5 .
• Holder N, Klein R . Eph receptors and ephrins: effectors of morphogenesis . Development . 126 . 10 . 2033–44 . 1999 . 10.1242/dev.126.10.2033 . 10207129 .
• Wilkinson DG . Eph receptors and ephrins: regulators of guidance and assembly . Int. Rev. Cytol. . 196 . 177–244 . 2000 . 10730216 . 10.1016/S0074-7696(00)96005-4 . International Review of Cytology . 9780123646002 .
• Xu Q, Mellitzer G, Wilkinson DG . Roles of Eph receptors and ephrins in segmental patterning . Philos. Trans. R. Soc. Lond. B Biol. Sci. . 355 . 1399 . 993–1002 . 2000 . 11128993 . 1692797 . 10.1098/rstb.2000.0635 .
• Wilkinson DG . Multiple roles of EPH receptors and ephrins in neural development . Nat. Rev. Neurosci. . 2 . 3 . 155–64 . 2001 . 11256076 . 10.1038/35058515 . 205014301 .
• Kinch MS, Carles-Kinch K . Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer . Clin. Exp. Metastasis . 20 . 1 . 59–68 . 2003 . 12650608 . 10.1023/A:1022546620495 . 2472961 .
• Walker-Daniels J, Hess AR, Hendrix MJ, Kinch MS . Differential regulation of EphA2 in normal and malignant cells . Am. J. Pathol. . 162 . 4 . 1037–42 . 2003 . 12651595 . 1851246 . 10.1016/S0002-9440(10)63899-0 .
• Lindberg RA, Hunter T . cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases . Mol. Cell. Biol. . 10 . 12 . 6316–24 . 1990 . 2174105 . 362907 . 10.1128/mcb.10.12.6316.
• Pandey A, Shao H, Marks RM, Polverini PJ, Dixit VM . Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis . Science . 268 . 5210 . 567–9 . 1995 . 7536959 . 10.1126/science.7536959 . 1995Sci...268..567P .
• Pandey A, Duan H, Dixit VM . Characterization of a novel Src-like adapter protein that associates with the Eck receptor tyrosine kinase . J. Biol. Chem. . 270 . 33 . 19201–4 . 1995 . 7543898 . 10.1074/jbc.270.33.19201 . free .
• Ruiz JC, Robertson EJ . The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development . Mech. Dev. . 46 . 2 . 87–100 . 1994 . 7918100 . 10.1016/0925-4773(94)90078-7 . 21419336 .
• Davis S, Gale NW, Aldrich TH, Maisonpierre PC, Lhotak V, Pawson T, Goldfarb M, Yancopoulos GD . Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity . Science . 266 . 5186 . 816–9 . 1994 . 7973638 . 10.1126/science.7973638 . 1994Sci...266..816D .
• Pandey A, Lazar DF, Saltiel AR, Dixit VM . Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity . J. Biol. Chem. . 269 . 48 . 30154–7 . 1994 . 10.1016/S0021-9258(18)43790-8 . 7982920 . free .
• Ganju P, Shigemoto K, Brennan J, Entwistle A, Reith AD . The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development . Oncogene . 9 . 6 . 1613–24 . 1994 . 8183555 .
• Gale NW, Holland SJ, Valenzuela DM, Flenniken A, Pan L, Ryan TE, Henkemeyer M, Strebhardt K, Hirai H, Wilkinson DG, Pawson T, Davis S, Yancopoulos GD . Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis . Neuron . 17 . 1 . 9–19 . 1996 . 8755474 . 10.1016/S0896-6273(00)80276-7 . 1075856 . free .
• Kozlosky CJ, VandenBos T, Park L, Cerretti DP, Carpenter MK . LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain . Cytokine . 9 . 8 . 540–9 . 1997 . 9245480 . 10.1006/cyto.1997.0199 .
• Ephnomenclaturecommittee . Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee . Cell . 90 . 3 . 403–4 . 1997 . 9267020 . 10.1016/S0092-8674(00)80500-0 . 26773768 . free .

Notes and References

1. Sulman EP, Tang XX, Allen C, Biegel JA, Pleasure DE, Brodeur GM, Ikegaki N . ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers . Genomics . 40 . 2 . 371–4 . April 1997 . 9119409 . 10.1006/geno.1996.4569 . free .
2. Web site: Entrez Gene: EPHA2 EPH receptor A2.
3. Web site: Counteracting Drug Resistance in Melanoma . 2015 . 2015-02-04 . 2015-02-04 . https://web.archive.org/web/20150204044952/http://www.oncotherapynetwork.com/skin-cancer-melanoma-targets/counteracting-drug-resistance-melanoma . dead .
4. Hahn AS, Kaufmann JK, Wies E, Naschberger E, Panteleev-Ivlev J, Schmidt K, Holzer A, Schmidt M, Chen J, König S, Ensser A, Myoung J, Brockmeyer NH, Stürzl M, Fleckenstein B, Neipel F . The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma–associated herpesvirus . Nat. Med. . 18 . 6 . 961–6 . 2012 . 22635007 . 3645317 . 10.1038/nm.2805 .
5. Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M, Nguyen M, Rajashankar KR, Wang BC, Nikolov DB . Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex . EMBO Rep . 10 . 7 . 722–8 . July 2009 . 19525919 . 10.1038/embor.2009.91 . 2727437 . free .
6. Kikawa KD, Vidale DR, Van Etten RL, Kinch MS . Regulation of the EphA2 kinase by the low molecular weight tyrosine phosphatase induces transformation . J. Biol. Chem. . 277 . 42 . 39274–9 . October 2002 . 12167657 . 10.1074/jbc.M207127200 . free .
7. Pratt RL, Kinch MS . Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade . Oncogene . 21 . 50 . 7690–9 . October 2002 . 12400011 . 10.1038/sj.onc.1205758 . 7083192 .
8. Pandey A, Lazar DF, Saltiel AR, Dixit VM . Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity . J. Biol. Chem. . 269 . 48 . 30154–7 . December 1994 . 10.1016/S0021-9258(18)43790-8 . 7982920 . free .
9. Petty A, Myshkin E, Qin H, Guo H, Miao H, Tochtrop GP, Hsieh JT, Page P, Liu L, Lindner DJ, Acharya C, MacKerell AD, Ficker E, Song J, Wang BC. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo . PLOS ONE . 7 . 8 . e42120 . August 2012 . 22916121 . 10.1371/journal.pone.0042120 . 3419725 . 2012PLoSO...742120P . free .