Disease relevance of Efna1

• Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2 [1].
• The formation of one such map, defined by the connection of ganglion cells in the retina to their targets in the superior colliculus of the midbrain, is thought to depend upon an interaction between complementary gradients of retinal EphA receptors and collicular ephrin-A ligands [2].
• Since EphA2 is required for ephrin-A1 ligand-induced vascular remodeling and is overexpressed in a variety of vascularized human adenocarcinomas, we assessed tumor angiogenesis and metastatic progression in EphA2-deficient host animals [3].
• Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines [4].

High impact information on Efna1

• In addition, expression of a mutant form of ephexin in primary neurons interferes with ephrin-A-induced growth cone collapse [5].
• Its sequence is homologous with B61, a ligand for the Eck kinase, defining a family of related ligands [6].
• Subsequently, supernatants from selected cell lines were fractionated directly by receptor affinity chromatography, resulting in the single-step purification of B61, a protein previously identified as the product of an early response gene induced by tumour necrosis factor-alpha [7].
• Axon guidance assays showed that SRF was a key mediator of ephrin-A and semaphorin guidance cues; in SRF-deficient neurons, these resulted in the formation of F-actin-microtubule rings rather than complete growth cone collapse [8].
• Notably, CT axons that mis-express EphA7 do not shift the relative positioning of their pathway within the subcortical telencephalon (ST), indicating that they do not depend upon EphA7/ephrin-A signaling in the ST for establishing this topography [9].

Biological context of Efna1

• These results demonstrate that ephrin-A1 suppresses T cell activation and Th2 cytokine expression, while preventing activation-induced cell death [10].
• Finally, the gene for B61 was localized to a specific position on mouse chromosome 3 by interspecific back-cross analysis [11].
• Gene expression screening showed decreased ephrin-A1 expression in CD4+ T cells of asthma patients [10].
• Analysis using EphA8 extracellular and intracellular domain mutants has revealed that enhanced cell adhesion is dependent on ephrin A binding to the extracellular domain and the juxtamembrane segment of the cytoplasmic domain of the receptor [12].
• Molecular cloning and expression of rat and mouse B61 gene: implications on organogenesis [13].

Anatomical context of Efna1

• In addition, ephrin-A1 and ephrin-A5 were seen in the forming blood vessels and alveolar bone, respectively [14].
• Prior to birth, ephrin-A1, ephrin-A5, EphA2, and EphA4 transcripts were present in the cuspal area of the dental papilla including the preodontoblasts [14].
• B61 was originally described as a novel secreted tumor necrosis factor-alpha-inducible gene product in endothelial cells (Holzman, L. B., Marks, R. M., and Dixit, V. M. (1990) Mol. Cell. Biol. 10, 5830-5838) [11].
• This study demonstrates significantly reduced ephrin-A1 expression in T cells of asthma patients using real time-PCR [10].
• Ephrin-A1 suppresses Th2 cell activation and provides a regulatory link to lung epithelial cells [10].

Associations of Efna1 with chemical compounds

• Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development [15].
• We provide evidence that Abl family kinases are a major effector of ephrin-A-induced retinal ganglion cell repulsion since the Abl inhibitor, STI571, prevents both loss of growth cone lamellipodia and axon retraction [16].
• When the GPI-linked protein B61 was inducibly expressed in these cells, sorting to caveolar membranes occurred normally, even in the presence of glucosylceramide depletion [17].

Regulatory relationships of Efna1

• We now show that B61 can also exist as a cell surface glycosylphosphatidyl-inositol-linked protein that is capable of activating the Eck receptor protein-tyrosine kinase, the first such report of a receptor protein-tyrosine kinase ligand that is glycosylphosphatidylinositol-linked [11].
• The majority of ephrin-A1-induced neurons is immunoreactive for tyrosine hydroxylase [18].
• In vitro treatment with soluble ephrin-A ligands similarly induced the rapid death of cultured dissociated cortical progenitors in a caspase-3-dependent manner, thereby confirming a direct effect of ephrin/Eph signalling on apoptotic cascades [19].
• Expression of dominant negative PI3-kinase or Rac1 inhibits ephrin-A1-induced endothelial cell migration [20].
• Moreover, the ephrin-A1-induced tyrosine phosphorylation of EphA4 was reduced in C2C12 myotubes after the blockade of ARMS and alpha-syntrophin expression by RNA interference [21].

Other interactions of Efna1

• Additionally, we have used a low-stringency PCR cloning technique to identify ligands, related to B61, that may interact with Eek [22].
• Characterization of B61, the ligand for the Eck receptor protein-tyrosine kinase [11].
• The expression of other members of this gene family, including ephrin-B2, EphA2, and ephrin-A1, in a compartmentalized pattern within the Purkinje cell layer suggests a possible redundancy and/or a compensation of EphA4 function in the segmental patterning of cerebellar Purkinje cells [23].
• In contrast, ephrin-A1 reduced the expression of fibronectin mRNA in C2C12 myotubes independently of Jak2 [24].
• Immunohistochemistry demonstrated that the expression of Eph A1 on endometrial epithelial cells and ephrin A1 and A3 expression on embryos decreased at implantation sites [25].

Analytical, diagnostic and therapeutic context of Efna1

• In addition, the expression patterns of B61 and Eck during mouse ontogeny were determined by in situ hybridization [11].
• By immunohistochemistry, the ephrin-A1 ligand and one of its receptors, EphA2, were detected throughout tumor vasculature [26].
• Furthermore, EphA2 was tyrosine-phosphorylated in the xenograft tumors, indicating that it was activated, presumably by interacting with ephrin-A1 [26].
• Sequence analysis has revealed that there is a considerable degree of identity among rat, mouse and human B61 (98.0% between rat and mouse, 86.3% between rat and human in amino acid level) [13].
• We have developed a co-culture assay to observe the dynamic cytoskeletal rearrangements comprising retinal growth cone collapse stimulated by contact with an ephrin-A-expressing fibroblast [16].

References