Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Ephrin Receptor A2

  • Chiara Allocca
  • Maria Domenica CastelloneEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101649



Historical Background

Erythropoietin-producing human hepatocellular carcinoma receptors (EPH) have been discovered through a screening aimed at identifying novel kinases involved in cancer (Holland et al. 1997). They form the largest subfamily of receptor tyrosine kinases (RTKs) and are among the oldest evolutionarily conserved receptor/ligand pairs (Pasquale 2008). EPH receptors and their ephrin (EFNs) ligands are expressed in all embryonic germ layers of vertebrates and mediate cell migration and positioning, boundary formation, and segmentation during important developmental processes such as gastrulation (Pasquale 2008). Axon guidance is one of the main functions of EPHs/EFNs; however, this system is nowadays regarded as a universal cell-to-cell communication pathway that allows cellular moving to a specific position and maintains cellular organization through chemotactic/chemorepulsive forces (Pasquale 2008; Genander 2012). Recent...

This is a preview of subscription content, log in to check access.


  1. Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR, Chen H, Cates JM, Colvin DC, Ye F, Brantley-Sieders DM, Cook RS, Tan L, Gray NS, Chen J. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest. 2014;124:2037–49.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Amato KR, Wang S, Tan L, Hastings AK, Song W, Lovly CM, Meador CB, Ye F, Lu P, Balko JM, Colvin DC, Cates JM, Pao W, Gray NS, Chen J. EPHA2 blockade overcomes acquired resistance to EGFR kinase inhibitors in lung cancer. Cancer Res. 2016;76:305–18.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Beauchamp A, Debinski W. Ephs and ephrins in cancer: ephrin-A1 signalling. Semin Cell Dev Biol. 2012;23:109–15.CrossRefPubMedGoogle Scholar
  4. Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, Coffman K, Jackson D, Bruckheimer E, Muraoka-Cook RS, Chen J. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest. 2008;118:64–78.CrossRefPubMedGoogle Scholar
  5. Davis TL, Walker JR, Allali-Hassani A, Parker SA, Turk BE, Dhe-Paganon S. Structural recognition of an optimized substrate for the ephrin family of receptor tyrosine kinases. FEBS J. 2009;276:4395–404.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Genander M. Eph and ephrins in epithelial stem cell niches and cancer. Cell Adhes Migr. 2012;6:126–30.CrossRefGoogle Scholar
  7. Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J. 1997;16:3877–88.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Larsen AB, Stockhausen MT, Poulsen HS. Cell adhesion and EGFR activation regulate EphA2 expression in cancer. Cell Signal. 2010;22:636–44.CrossRefPubMedGoogle Scholar
  9. Macrae M, Neve RM, Rodriguez-Viciana P, Haqq C, Yeh J, Chen C, Gray JW, McCormick F. A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell. 2005;8:111–8.CrossRefPubMedGoogle Scholar
  10. 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;2:62–9.CrossRefPubMedGoogle Scholar
  11. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, Rhim JS, Sedor JR, Burnett E, Wang B. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001;3:527–30.CrossRefPubMedGoogle Scholar
  12. Miao H, Li D, Mukherjee A, Guo H, Cutter J, Basilon JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B. EphA2 mediates ligand-dependent inihibition and ligand-indipendent promotion of cell-migration and invasion via reciprocal regulatory loop with Akt. Cancer Cell. 2009;16:9–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Miao H, Gale NW, Guo H, Qian J, Petty A, Kaspar J, Murphy AJ, Valenzuela DM, Yancopoulos G, Hambardzumyan D, Lathia JD, Rich JN, Lee J, Wang B. EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties. Oncogene. 2015a;34:558–67.CrossRefPubMedGoogle Scholar
  14. Miao B, Ji Z, Tan L, Taylor M, Zhang J, Choi HG, Frederick DT, Kumar R, Wargo JA, Flaherty KT, Gray NS, Tsao H. EPHA2 is a mediator of vemurafenib resistance and a novel therapeutic target in melanoma. Cancer Discov. 2015b;5:274–87.CrossRefPubMedGoogle Scholar
  15. Minami M, Koyama T, Wakayama Y, Fukuhara S, Mochizuki N. EphrinA/EphA signal facilitates insulin-like growth factor-I-induced myogenic differentiation through suppression of the Ras/extracellular signal-regulated kinase 1/2 cascade in myoblast cell lines. Mol Biol Cell. 2011;22:3508–19.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133:38–52.CrossRefPubMedGoogle Scholar
  17. Perez White BE, Getsios S. Eph receptor and ephrin function in breast, gut, and skin epithelia. Cell Adhes Migr. 2014;8:327–38.CrossRefGoogle Scholar
  18. Tanaka M, Kamata R, Sakai R. EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability. J Biol Chem. 2005;280:42375–82.CrossRefPubMedGoogle Scholar
  19. Wakayama Y, Miura K, Sabe H, Mochizuki N. EphrinA1-EphA2 signal induces compaction and polarization of Madin-Darby canine kidney cells by inactivating Ephrin through negative regulation of RhoA. J Biol Chem. 2011;286:44243–53.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Zhou Y, Yamada N, Tanaka T, Hori T, Yokoyama S, Hayakawa Y, Yano S, Fukuoka J, Koizumi K, Saiki I, Sakurai H. Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2. Nat Commun. 2015;6:7679.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular Medicine and Medical BiotechnologiesUniversity of Naples “Federico II”NaplesItaly
  2. 2.Institute of Experimental Endocrinology and Oncology (IEOS)CNRNaplesItaly