3hei

Structural highlights

Disease

[EPHA2_HUMAN] Genetic variations in EPHA2 are the cause of susceptibility to cataract cortical age-related type 2 (ARCC2) [MIM:613020]. A developmental punctate opacity common in the cortex and present in most lenses. The cataract is white or cerulean, increases in number with age, but rarely affects vision.^{[1] [2]} Defects in EPHA2 are the cause of cataract posterior polar type 1 (CTPP1) [MIM:116600]. A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity.^{[3] [4] [5] [6]} Note=Overexpressed in several cancer types and promotes malignancy.^[7]

Function

[EPHA2_HUMAN] Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis.^{[8] [9] [10] [11] [12] [13]} [EFNA1_HUMAN] Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. Plays an important role in angiogenesis and tumor neovascularization. The recruitment of VAV2, VAV3 and PI3-kinase p85 subunit by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly. Exerts anti-oncogenic effects in tumor cells through activation and down-regulation of EPHA2. Activates EPHA2 by inducing tyrosine phosphorylation which leads to its internalization and degradation. Acts as a negative regulator in the tumorigenesis of gliomas by down-regulating EPHA2 and FAK. Can evoke collapse of embryonic neuronal growth cone and regulates dendritic spine morphogenesis.^{[14] [15]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Ephrin
• Ephrin receptor

References

1. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. 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. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
2. ↑ Jun G, Guo H, Klein BE, Klein R, Wang JJ, Mitchell P, Miao H, Lee KE, Joshi T, Buck M, Chugha P, Bardenstein D, Klein AP, Bailey-Wilson JE, Gong X, Spector TD, Andrew T, Hammond CJ, Elston RC, Iyengar SK, Wang B. EPHA2 is associated with age-related cortical cataract in mice and humans. PLoS Genet. 2009 Jul;5(7):e1000584. doi: 10.1371/journal.pgen.1000584. Epub 2009 , Jul 31. PMID:19649315 doi:10.1371/journal.pgen.1000584
3. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. 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. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
4. ↑ Shiels A, Bennett TM, Knopf HL, Maraini G, Li A, Jiao X, Hejtmancik JF. The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008;14:2042-55. Epub 2008 Nov 12. PMID:19005574
5. ↑ Zhang T, Hua R, Xiao W, Burdon KP, Bhattacharya SS, Craig JE, Shang D, Zhao X, Mackey DA, Moore AT, Luo Y, Zhang J, Zhang X. Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum Mutat. 2009 May;30(5):E603-11. doi: 10.1002/humu.20995. PMID:19306328 doi:10.1002/humu.20995
6. ↑ Park JE, Son AI, Hua R, Wang L, Zhang X, Zhou R. Human cataract mutations in EPHA2 SAM domain alter receptor stability and function. PLoS One. 2012;7(5):e36564. doi: 10.1371/journal.pone.0036564. Epub 2012 May 3. PMID:22570727 doi:10.1371/journal.pone.0036564
7. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. 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. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
8. ↑ Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000 Feb;2(2):62-9. PMID:10655584 doi:10.1038/35000008
9. ↑ Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005 Dec 23;280(51):42375-82. Epub 2005 Oct 18. PMID:16236711 doi:10.1074/jbc.M503786200
10. ↑ Zhang G, Njauw CN, Park JM, Naruse C, Asano M, Tsao H. EphA2 is an essential mediator of UV radiation-induced apoptosis. Cancer Res. 2008 Mar 15;68(6):1691-6. doi: 10.1158/0008-5472.CAN-07-2372. PMID:18339848 doi:10.1158/0008-5472.CAN-07-2372
11. ↑ Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. 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. doi: 10.1016/j.ccr.2009.04.009. PMID:19573808 doi:10.1016/j.ccr.2009.04.009
12. ↑ Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol. 2010 Aug 9;190(3):461-77. doi: 10.1083/jcb.201005141. Epub 2010 Aug , 2. PMID:20679435 doi:10.1083/jcb.201005141
13. ↑ Lin S, Gordon K, Kaplan N, Getsios S. Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1. Mol Biol Cell. 2010 Nov 15;21(22):3902-14. doi: 10.1091/mbc.E10-03-0242. Epub, 2010 Sep 22. PMID:20861311 doi:10.1091/mbc.E10-03-0242
14. ↑ Liu DP, Wang Y, Koeffler HP, Xie D. Ephrin-A1 is a negative regulator in glioma through down-regulation of EphA2 and FAK. Int J Oncol. 2007 Apr;30(4):865-71. PMID:17332925
15. ↑ Wykosky J, Palma E, Gibo DM, Ringler S, Turner CP, Debinski W. 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. doi: 10.1038/onc.2008.328. Epub 2008 Sep, 15. PMID:18794797 doi:10.1038/onc.2008.328
16. ↑ Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M, Nguyen M, Rajashankar KR, Wang B, 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. 2009 Jul;10(7):722-8. Epub 2009 Jun 12. PMID:19525919 doi:10.1038/embor.2009.91