Ephrin A5

Ephrin-A5
PDB rendering based on 1shw.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2X11​, 3MX0​, 4BK5​, 4BKA​, 4L0P​, 4M4R​
Identifiers
Symbols	EFNA5 ; AF1; EFL5; EPLG7; GLC1M; LERK7; RAGS
External IDs	OMIM: 601535 MGI: 107444 HomoloGene: 1482 GeneCards: EFNA5 Gene
Gene ontology Molecular function • chemorepellent activity • ephrin receptor binding Cellular component • extracellular region • plasma membrane • caveola • anchored component of external side of plasma membrane Biological process • apoptotic process • nervous system development • axon guidance • regulation of cell-cell adhesion • retinal ganglion cell axon guidance • regulation of actin cytoskeleton organization • regulation of GTPase activity • ephrin receptor signaling pathway • positive regulation of peptidyl-tyrosine phosphorylation • negative chemotaxis • regulation of focal adhesion assembly • regulation of insulin secretion involved in cellular response to glucose stimulus • regulation of microtubule cytoskeleton organization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1946	13640
Ensembl	ENSG00000184349	ENSMUSG00000048915
UniProt	P52803	O08543
RefSeq (mRNA)	NM_001962	NM_010109
RefSeq (protein)	NP_001953	NP_034239
Location (UCSC)	Chr 5: 107.38 – 107.67 Mb	Chr 17: 62.6 – 62.88 Mb
PubMed search

Ephrin A5 is a protein that in humans is encoded by the EFNA5 gene.^[1][2][3]

Ephrin A5 is a glycosylphosphatidylinositol (GPI)-anchored protein of the ephrin-A subclass of ephrin ligands that binds to the EphA subclass of Eph receptors. Ephrin A5 has also been shown to bind to the EphB2 receptor.^[4]

Reverse signaling in growth cone survival

"Reverse" signaling is one unique property of ephrin ligands that allows for the transmission of an intracellular signal in ephrin-expressing cells that is distinct from the signal transmitted in Eph receptor-expressing cells. Although the mechanism of "reverse" signaling by ephrin-As is not well understood, it is relatively surprising considering that ephrin-A ligands are attached to the cell membrane solely by a GPI linkage and unlike ephrin-Bs, lack a potential intracellular signaling domain. Nonetheless, certain ephrin-A ligands are known to initiate reverse signaling cascades like ephrin A5, which has been shown to stimulate the spreading of growth cones in cultures of mouse spinal motor neurons.^[5] Interestingly, reverse signaling by ephrin A5 was demonstrated to be GPI-dependent as the elimination of all GPI linkages by the application of a phosphatidlyinositol-specific phospholipase C abolished the positive effects of ephrin A5 on growth cone spreading. Additionally, EphA receptors were shown to exert opposite effects on motor neuron growth cones by reducing growth cone size.

Formation of the retinotopic map

This finding that ephrin A5 promotes growth cone survival that is opposite of EphA signaling and mediated directly by ephrin A5 reverse signaling has important implications for axon guidance as it provides a mechanism by which migrating axons expressing EphAs would preferentially avoid ephrin A5 expressing cells and possibly migrate towards cells with lower expression of ephrin A5.^[5] This mechanism is in fact the same one that mediates the guidance of retinal ganglion cells to distinct regions in the superior colliculus during the formation of the retinotopic map. High ephrin A5 expression on cells in the posterior region of the SC bind to EphAs expressed in RGCs migrating from the temporal retina, inducing growth cone collapse and repelling these RGCs away from the posterior SC towards a region of low ephrin A5 expression in the anterior SC.^[6]

References

1. Cerretti DP, Copeland NG, Gilbert DJ, Jenkins NA, Kuefer MU, Valentine V, Shapiro DN, Cui X, Morris SW (Sep 1996). "The gene encoding LERK-7 (EPLG7, Epl7), a ligand for the Eph-related receptor tyrosine kinases, maps to human chromosome 5 at band q21 and to mouse chromosome 17". Genomics 35 (2): 376–9. doi:10.1006/geno.1996.0371. PMID 8661153.
2. Kozlosky CJ, VandenBos T, Park L, Cerretti DP, Carpenter MK (Oct 1997). "LERK-7: a ligand of the Eph-related kinases is developmentally regulated in the brain". Cytokine 9 (8): 540–9. doi:10.1006/cyto.1997.0199. PMID 9245480.
3. "Entrez Gene: EFNA5 ephrin-A5".
4. Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (May 2004). "Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling". Nat. Neurosci. 7 (5): 501–9. doi:10.1038/nn1237. PMID 15107857.
5. Marquardt T, Shirasaki R, Ghosh S, Andrews SE, Carter N, Hunter T, Pfaff SL (April 2005). "Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains". Cell 121 (1): 127–39. doi:10.1016/j.cell.2005.01.020. PMID 15820684.
6. Drescher U, Kremoser C, Handwerker C, Löschinger J, Noda M, Bonhoeffer F (August 1995). "In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases". Cell 82 (3): 359–70. doi:10.1016/0092-8674(95)90425-5. PMID 7634326.

Further reading

• Flanagan JG, Vanderhaeghen P (1998). "The ephrins and Eph receptors in neural development". Annu. Rev. Neurosci. 21: 309–45. doi:10.1146/annurev.neuro.21.1.309. PMID 9530499.
• Zhou R (1998). "The Eph family receptors and ligands". Pharmacol. Ther. 77 (3): 151–81. doi:10.1016/S0163-7258(97)00112-5. PMID 9576626.
• Holder N, Klein R (1999). "Eph receptors and ephrins: effectors of morphogenesis". Development 126 (10): 2033–44. PMID 10207129.
• Wilkinson DG (2000). "Eph receptors and ephrins: regulators of guidance and assembly". Int. Rev. Cytol. International Review of Cytology 196: 177–244. doi:10.1016/S0074-7696(00)96005-4. ISBN 978-0-12-364600-2. PMID 10730216.
• Xu Q, Mellitzer G, Wilkinson DG (2001). "Roles of Eph receptors and ephrins in segmental patterning". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 355 (1399): 993–1002. doi:10.1098/rstb.2000.0635. PMC 1692797. PMID 11128993.
• Wilkinson DG (2001). "Multiple roles of EPH receptors and ephrins in neural development". Nat. Rev. Neurosci. 2 (3): 155–64. doi:10.1038/35058515. PMID 11256076.
• Winslow JW, Moran P, Valverde J, et al. (1995). "Cloning of AL-1, a ligand for an Eph-related tyrosine kinase receptor involved in axon bundle formation". Neuron 14 (5): 973–81. doi:10.1016/0896-6273(95)90335-6. PMID 7748564.
• Gale NW, Holland SJ, Valenzuela DM, et al. (1996). "Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis". Neuron 17 (1): 9–19. doi:10.1016/S0896-6273(00)80276-7. PMID 8755474.
• Lackmann M, Mann RJ, Kravets L, et al. (1997). "Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor". J. Biol. Chem. 272 (26): 16521–30. doi:10.1074/jbc.272.26.16521. PMID 9195962.
• Ephnomenclaturecommittee, (1997). "Unified nomenclature for Eph family receptors and their ligands, the ephrins. Eph Nomenclature Committee". Cell 90 (3): 403–4. doi:10.1016/S0092-8674(00)80500-0. PMID 9267020.
• Ciossek T, Monschau B, Kremoser C, et al. (1998). "Eph receptor-ligand interactions are necessary for guidance of retinal ganglion cell axons in vitro". Eur. J. Neurosci. 10 (5): 1574–80. doi:10.1046/j.1460-9568.1998.00180.x. PMID 9751130.
• Janis LS, Cassidy RM, Kromer LF (1999). "Ephrin-A binding and EphA receptor expression delineate the matrix compartment of the striatum". J. Neurosci. 19 (12): 4962–71. PMID 10366629.
• Gerlai R, Shinsky N, Shih A, et al. (1999). "Regulation of learning by EphA receptors: a protein targeting study". J. Neurosci. 19 (21): 9538–49. PMID 10531456.
• Davy A, Gale NW, Murray EW, et al. (2000). "Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion". Genes Dev. 13 (23): 3125–35. doi:10.1101/gad.13.23.3125. PMC 317175. PMID 10601038.