Disease relevance of Epha4

• These antibodies, together with the expression of the Sek-1 gene in a baculovirus system, were instrumental in demonstrating that the protein carries a tyrosine kinase activity and that it is presented at the cell surface with its N-terminal (putative ligand-binding) domain outside of the cell [1].

High impact information on Epha4

• Mek4 and Sek are tyrosine kinases with expression patterns in the mouse embryo that suggest important functions in early development [2].
• Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases [2].
• Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism [3].
• EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract [4].
• The expression of the hindbrain markers Krox20 and Epha4 was altered in Msx1/2 mutants, suggesting that defects in neural crest populations may result, in part, from defects in rhombomere identity [5].

Biological context of Epha4

• These data are consistent with a role of the Sek gene product in a signal transduction process involved in pattern formation in the hindbrain [6].
• This disruption is rescued by full-length Sek-1, indicating a requirement for the kinase domain in the segmental restriction of gene expression [7].
• We have now identified two in vitro autophosphorylation sites within the juxtamembrane domain of the Eph family member Sek, and a candidate binding protein for the activated Sek kinase [8].
• After segmentation of the vertebrate hindbrain, expression of the zinc-finger gene Krox-20 and the receptor tyrosine kinase gene Sek-1 is precisely restricted to rhombomeres (r) 3 and 5 [9].
• Therefore, as expected from its amino acid sequence, Sek-1 conforms to the general model of receptor-type tyrosine kinases [1].

Anatomical context of Epha4

• Segmental expression of the EphA4 (Sek-1) receptor tyrosine kinase in the hindbrain is under direct transcriptional control of Krox-20 [10].
• In addition, Sek expression occurs in several other developing tissues, including a dynamic regulation in the developing forebrain, spinal cord, early mesoderm and anterior presomitic mesoderm (segmental plate) [11].
• Sek expression initially occurs throughout the presumptive somite, then becomes restricted anteriorly, and finally is down-regulated as the definitive somite is formed [11].
• Expression and regulation of Cek-8, a cell to cell signalling receptor in developing chick limb buds [12].
• Later on in limb development, Cek-8 expression is associated with cell condensations that form tendons and their attachments to cartilage rudiments and then in developing feather buds [12].

Associations of Epha4 with chemical compounds

• Expression of Cek-8 in distal mesenchyme is regulated by apical ridge- and FGF-polarising signals and retinoic acid, and is uniform across the anteroposterior axis in talpid3 mutants [12].
• RESULT: With our newly developed liposome, GTE 319 and GTE 321, the lac-Z gene was more efficiently transfected in cisplatin-resistant variant cells, mEIIL-R, KF-ra and KF-rb, than in parental cells, mEIIL and KF, using X-gal staining [13].

Other interactions of Epha4

• We show that Mek4 and Sek soluble receptor-alkaline phosphatase fusion proteins can be used in a procedure termed RAP in situ to identify regions of ligand expression in the mouse embryo [2].
• Together with our previous finding that Sek (Sek-1) is expressed in r3 and r5 (Gilardi-Hebenstreit et al., 1992; Nieto et al., 1992), these data indicate that members of the Eph family of RTKs may co-operate in the segmental patterning of the hindbrain [14].
• In contrast, the expression of EphA4 (Epha4), lunatic fringe or protocadherin, thought to be involved in segment border formation, was fairly normal in hypomorphic mutant embryos [15].
• Purkinje cells in each domain exhibit a domain-specific expression profile of genes, including Bmp-7, EphA5/Cek-7, EphA4/Cek-8, and several chick homologs of Drosophila segmentation genes [16].
• The expression domain of cMespo in PSM largely overlaps with delta-1 but spares a region of several prospective somites at the rostral end of PSM in which c-Meso and Cek-8 are expressed [17].

Analytical, diagnostic and therapeutic context of Epha4

• In situ hybridization analysis revealed that one of these genes, Sek, was expressed in an alternating segment-restricted pattern in the developing hindbrain [6].
• Two dimensional phosphopeptide mapping and site-directed mutagenesis defined juxtamembrane residue Y602 as a major site of in vitro autophosphorylation in Sek, whilst Y596 was phosphorylated to a lower stoichiometry [8].
• We have analysed Krox-20 and Sek-1 expression in the mouse and chick hindbrain at single-cell resolution using whole-mount in situ hybridisation and immunocytochemistry [9].

References