High impact information on Epha8

• We have generated mice homozygous for a mutation that disrupts the gene encoding EphA8, a member of the Eph family of tyrosine protein kinase receptors, previously known as Eek [1].
• The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner [2].
• 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 [2].
• Interestingly, a kinase-inactive EphA8 mutant also markedly promoted cell attachment to fibronectin in these cell lines [2].
• Treatment with various inhibitors further reveals that the mitogen-activated protein kinase (MAPK) signaling pathway is critical for neurite outgrowth induced by EphA8 [3].

Biological context of Epha8

• We therefore propose that Fyn kinase is one of the major downstream targets for the EphA8 signaling pathway leading to a modification of cell adhesion, and that autophosphorylation at Tyr-838 is critical for positively regulating the EphA8 signaling event [4].
• Finally, it was observed that cell attachment responses are attenuated by overexpression of wild type EphA8 receptor but to much less extent by EphA8 mutants lacking phosphorylation at either Tyr-615 or Tyr-838 [4].
• The gene encoding the mouse EphA8 receptor tyrosine kinase has been isolated from a mouse genomic library, and its complete genomic structure has been determined [5].
• Finally, in situ RNA hybridization studies revealed a very specific pattern of EphA8 gene expression restricted to the rostral region of midbrain tectum during embryonic development [5].
• The putative promoter of the EphA8 gene lacks a TATA box and contains multiple copies of the sequence GGGCGG, the core sequence of the putative Sp1-binding site [5].

Anatomical context of Epha8

• Taken together, these results suggest the presence of a novel mechanism by which the EphA8 receptor localizes p110gamma PI 3-kinase to the plasma membrane in a tyrosine kinase-independent fashion, thereby allowing access to lipid substrates to enable the signals required for integrin-mediated cell adhesion [2].
• In this report, we show that the EphA8 receptor induces neurite outgrowth in NG108-15 cells in the absence of ligand stimulation [3].
• In this study, we have examined if there are other additional ephrin ligands interacting with the EphA8 receptor tyrosine kinase expressed in NIH3T3 fibroblasts [6].

Associations of Epha8 with chemical compounds

• Aberrant axonal projections in mice lacking EphA8 (Eek) tyrosine protein kinase receptors [1].

Physical interactions of Epha8

• In vitro binding experiments revealed that phosphorylation at Tyr-615 in EphA8 mediates the preferential binding to Fyn-SH2 domain rather than Src and Ras GTPase-activating protein (Ras GAP)-SH2 domains [4].
• In vitro binding experiments revealed that the EphA8 juxtamembrane segment was sufficient for the formation of a stable complex with p110gamma [2].

Other interactions of Epha8

• Additionally, we have used a low-stringency PCR cloning technique to identify ligands, related to B61, that may interact with Eek [7].
• In this study, we have isolated a full-length cDNA, encoding the mouse homologue of a previous partially characterized Eek protein, a member of Eph receptor tyrosine kinase family [7].
• In contrast, the association of full-length Fyn to EphA8 containing mutation at either Tyr-615 or Tyr-838 was greatly reduced [4].
• It was previously shown that ephrin-A2, -A3 and -A5 bind to, and activate the EphA8 receptor tyrosine kinase, respectively [6].

References