Alternative titles; symbols
HGNC Approved Gene Symbol: EFNA1
Cytogenetic location: 1q22 Genomic coordinates (GRCh38): 1:155,127,876-155,134,899 (from NCBI)
EFNA1 is a member of the subfamily of ligands that bind to the EPH group of receptor tyrosine kinases. These so-called LERK proteins, also called ephrins, share sequence similarity and are attached to the cell membrane by glycosylphosphatidylinositol (GPI) linkages or by a single transmembrane domain (Cerretti et al., 1996).
See 179610 for additional information on ephrins and the Eph receptor family.
Holzman et al. (1990) characterized the product of B61, one of 3 novel genes whose expression in human umbilical vein endothelial cells is induced by tumor necrosis factor-alpha in the presence of cycloheximide (see 191163). Southern analysis suggested that it is an evolutionarily conserved single-copy gene. Although primarily a hydrophilic molecule, it contained both a hydrophobic N-terminal and a hydrophobic C-terminal region. The N-terminal region was typical of a signal peptide, which is consistent with the secreted nature of the protein. The mature form of the predicted protein consists of 187 amino acid residues with a predicted molecular weight of 22,000.
Davis et al. (1994) cloned B61 from a human SH-SY5Y neuroblastoma cell line cDNA library. The deduced 206-amino acid protein contains an N-terminal signal sequence, followed by a predicted receptor tyrosine kinase-binding domain and a C-terminal hydrophobic tail predicted to bind GPI. Northern blot analysis of rat tissues detected high B61 expression in liver, kidney, lung, muscle, heart, ad skin, but not in spleen or thymus or any neuronal tissue examined. B61 expression was weak in embryonic rat brain and absent in whole adult brain. B61 was expressed on the cell surface of transfected COS cells, and treatment of cells with phospholipase C (see 172420) released B61, consistent with its membrane association via a GPI linkage.
By expression cloning in COS cells, Davis et al. (1994) found that human B61 and EHK1L (EFNA3; 601381) bound to the receptor tyrosine kinase EHK1 (EPHA5; 600004), but not to ELK (EPHB1; 600600).
Pandey et al. (1995) presented evidence that LERK1 is involved in TNF-alpha (191160)-induced angiogenesis.
To examine the roles of EphA receptors and ephrin-A ligands in neuronal migration in the neocortex, Torii et al. (2009) analyzed Efna1/Efna3/Efna5 (601535) triple-knockout mice. These genes account for almost all ephrin-A genes in the developing neocortex. Most analyses were performed at postnatal day 0 or embryonic stages before the establishment of potentially mistargeted afferent and efferent projections. Torii et al. (2009) showed that an EphA and ephrin A (Efna) signaling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns in the neocortex. In contrast to the relatively uniform labeling of the developing cortical plate by various molecular markers and retrograde tracers in wildtype mice, they found alternating labeling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and Efnas during neuronal migration. Torii et al. (2009) concluded that this theretofore unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization.
Salaita et al. (2010) reconstituted the intermembrane signaling geometry between live EPHA2 (176946)-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EPHA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EPHA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease-10 (MMP10; 185260). Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines revealed characteristic differences that strongly correlated with invasion potential.
Cerretti et al. (1996) mapped the EPLG1 gene by fluorescence in situ hybridization to a cluster on chromosome 1q21-q22, together with EPLG3 (EFNA3; 601381) and EPLG4 (EFNA4; 601380). By interspecific backcross analysis they mapped the mouse homolog to the central region of mouse chromosome 3.
Cerretti, D. P., Lyman, S. D., Kozlosky, C. J., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Valentine, V., Kirstein, M. N., Shapiro, D. N., Morris, S. W. The genes encoding the Eph-related receptor tyrosine kinase ligands LERK-1 (EPLG1, Epl1), LERK-3 (EPLG3, Epl3), and LERK-4 (EPLG4, Epl4) are clustered on human chromosome 1 and mouse chromosome 3. Genomics 33: 277-282, 1996. [PubMed: 8660976] [Full Text: https://doi.org/10.1006/geno.1996.0192]
Davis, S., Gale, N. W., Aldrich, T. H., Maisonpierre, P. C., Lhotak, V., Pawson, T., Goldfarb, M., Yancopoulos, G. D. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266: 816-819, 1994. [PubMed: 7973638] [Full Text: https://doi.org/10.1126/science.7973638]
Holzman, L. B., Marks, R. M., Dixit, V. M. A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein. Molec. Cell. Biol. 10: 5830-5838, 1990. [PubMed: 2233719] [Full Text: https://doi.org/10.1128/mcb.10.11.5830-5838.1990]
Pandey, A., Lindberg, R. A., Dixit, V. M. Receptor orphans find a family. Curr. Biol. 5: 986-989, 1995. [PubMed: 8542290] [Full Text: https://doi.org/10.1016/s0960-9822(95)00195-3]
Salaita, K., Nair, P. M., Petit, R. S., Neve, R. M., Das, D., Gray, J. W., Groves, J. T. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 327: 1380-1385, 2010. [PubMed: 20223987] [Full Text: https://doi.org/10.1126/science.1181729]
Torii, M., Hashimoto-Torii, K., Levitt, P., Rakic, P. Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling. Nature 461: 524-528, 2009. Note: Erratum: Nature 462: 674 only, 2009. [PubMed: 19759535] [Full Text: https://doi.org/10.1038/nature08362]