Ephrin receptors

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Kinase - domain of the human Ephrin type A receptor 5 (EphA5)

Ephrin receptors (English Eph receptor , Eph) are receptors that are activated by binding ephrins. They form the largest known subfamily of receptor tyrosine kinases (RTK). Both ephrin receptors and their ligands are membrane proteins that require direct contact between cells for activation . Ephrin-dependent signal transduction is being investigated in relation to embryogenesis , the polarization of the direction of growth of axons , and cell migration and segmentation. Furthermore, an influence on various processes in adults, e.g. B. found in long-term potentiation , angiogenesis , differentiation of stem cells and cancer .

Ephrin receptor subclasses

Ephrin receptors are divided into two subclasses, EphA and EphB ( Gene EPHA and EPHB ), based on their binding affinity for glycosylphosphatidylinositol- anchored Ephrin A ligands or the transmembrane Ephrin B ligands. Of the sixteen ephrin receptors discovered in animals, only nine have EphA (EphA1-8 and EphA10) and five EphB (EphB1-4 and EphB6). Ephrins bind specifically within their subclass. Exceptions are the binding of Ephrin-B3 to Eph-A4 and the binding of Ephrin-A5 to Eph-B2. The binding within subclass A is mostly more specific than subclass B, which is attributed to the fact that the binding in subclass A is based on a key-lock principle with fewer conformational changes than in subclass B with an induced fit .

The following 16 ephrin receptors were found in animals: EPHA1 , EPHA2 , EPHA3 , EPHA4 , EPHA5 , EPHA6 , EPHA7 , EPHA8 , EPHA9 , EPHA10 * EPHB1 , EPHB2 , EPHB3 , EPHB4 , EPHB5 , EPHB6

activation

The extracellular domain of the ephrin receptor consists of a conserved globular ephrin binding domain, a cysteine- rich region and two fibronectin type 3 domains. The cytoplasmic part consists of a membrane-bordering kinase domain with two tyrosines , a sterile alpha motif (SAM) and a PDZ domain- binding motif. After binding a ligand, tyrosine and serine are phosphorylated at the ephrin receptor , which activates the tyrosine kinase function.

In contrast to most other receptor tyrosine kinases, ephrin receptors have the unique property of triggering signal transduction in both cells involved. Presumably this is a reason for the different effects triggered after activation of the ephrin receptors, e.g. B. on the survival of growth cones , or the separation of ephrin and ephrin receptor-expressing cells.

history

Ephrin receptors were first identified in 1987 in the search for RTK related to cancer in the cell line erythropoietin-producing hepatocellular carcinoma .

After it could be shown that almost all ephrin receptors occur in different stages of development as well as spatially limited, ephrin receptors became known as the main receptors for cell control during the development of invertebrates and vertebrates.

Individual evidence

  1. ^ N. Rohani, L. Canty, O. Luu, F. Fagotto, R. Winklbauer: EphrinB / EphB signaling controls embryonic germ layer separation by contact-induced cell detachment. In: PLoS Biol . Volume 9 (3), 2011, p. E1000597. PMID 21390298 ; PMC 3046958 (free full text).
  2. ^ A. Davy, P. Soriano: Ephrin signaling in vivo: look both ways. In: Dev Dyn. Volume 232 (1), 2005, pp. 1-10. PMID 15580616 .
  3. ↑ a b c K. Kullander, R. Klein: Mechanisms and functions of Eph and ephrin signaling. In: Nat Rev Mol Cell Biol . Volume 3 (7), 2002, pp. 475-486. PMID 12094214 .
  4. ^ S. Kuijper, CJ Turner, RH Adams: Regulation of angiogenesis by Eph-ephrin interactions. In: Trends Cardiovasc Med. Volume 17 (5), 2007, pp. 145-151. PMID 17574121 .
  5. ↑ M. Genander, J. Frisén: Ephrins and Eph receptors in stem cells and cancer. In: Curr Opin Cell Biol. Volume 22 (5), 2010, pp. 611-616. PMID 20810264 .
  6. ↑ Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee. In: Cell . Volume 90 (3), 1997, pp. 403-404. PMID 9267020 .
  7. ↑ ME Pitulescu, RH Adams: Eph / ephrin molecules - a hub for signaling and endocytosis. In: Genes Dev. Volume 24 (22), 2010, pp. 2480-2492. PMID 21078817 ; PMC 2975924 (free full text).
  8. ^ EB Pasquale: The Eph family of receptors. In: Curr Opin Cell Biol. Volume 9 (5), 1997, pp. 608-615. PMID 9330863 .
  9. ↑ JP Himanen, MJ Chumley, M. Lackmann, C. Li, WA Barton, PD Jeffrey, C. Vearing, D. Geleick, DA Feldheim, AW Boyd, M. Henkemeyer, DB Nikolov: Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. In: Nat Neurosci . Volume 7 (5), 2004, pp. 501-509. PMID 15107857 .
  10. ↑ a b J. P. Himanen: Ectodomain structures of Eph receptors. In: Semin Cell Dev Biol. Volume 23 (1), 2012, pp. 35-42. PMID 22044883 .
  11. ↑ MS Kalo, EB Pasquale: Multiple in vivo tyrosine phosphorylation sites in EphB receptors. In: Biochemistry . Volume 38 (43), 1999, pp. 14396-1408. PMID 10572014 .
  12. ↑ AC McClelland, M. Hruska, AJ Coenen, M. Henkemeyer, MB Dalva: Trans-synaptic EphB2-ephrin-B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling. In: Proc Natl Acad Sci USA . Volume 107 (19), 2010, pp. 8830-8835. PMID 20410461 ; PMC 2889310 (free full text).
  13. ^ IO Daar: Non-SH2 / PDZ reverse signaling by ephrins. In: Semin Cell Dev Biol. Volume 23 (1), 2012, pp. 65-74. PMID 22040914 . PMC 3288889 (free full text).
  14. ↑ T. Marquardt, R. Shirasaki, S. Ghosh, SE Andrews, N. Carter, T. Hunter, SL Pfaff: Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. In: Cell. Volume 121 (1), 2005, pp. 127-139. PMID 15820684 .
  15. ↑ C. Jørgensen, A. Sherman, GI Chen, A. Pasculescu, A. Poliakov, M. Hsiung, B. Larsen, DG Wilkinson, R. Linding, T. Pawson: Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells. In: Science . Volume 326 (5959), 2009, pp. 1502-1509. PMID 20007894 .
  16. ↑ KK Murai, EB Pasquale: Eph'ective signaling: forward, reverse and crosstalk . In: Journal of Cell Science . tape 116 , Pt 14, 2003, p. 2823-2832 , doi : 10.1242 / jcs.00625 , PMID 12808016 .
  17. ^ JG Flanagan, P. Vanderhaeghen: The ephrins and Eph receptors in neural development . In: Annual Review of Neuroscience . tape 21 , 1998, pp. 309-345 , doi : 10.1146 / annurev.neuro.21.1.309 , PMID 9530499 .
  18. ↑ AW Boyd, M. Lackmann: Signals from Eph and ephrin proteins: a developmental tool kit . In: Science's STKE: signal transduction knowledge environment . tape 2001 , no. 112 , 2001, ISSN  1525-8882 , p. RE20 , doi : 10.1126 / stke.2001.112.re20 , PMID 11741094 .

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