Disease relevance of Epha2

• The present study characterized a mutation in the Eck receptor tyrosine kinase gene induced by the U3betageo gene trap retrovirus [1].
• This is identical to the pattern of Eck gene expression as determined by either in situ hybridization or immunostaining, suggesting that expression of the Eck promoter was not affected by provirus integration [1].
• EphA2 (Eck) is a tyrosine kinase receptor that is overexpressed in several human cancers such as breast, colon, lung, prostate, gastric carcinoma, and metastatic melanoma but not in nonmalignant counterparts [2].

High impact information on Epha2

• Its sequence is homologous with B61, a ligand for the Eck kinase, defining a family of related ligands [3].
• By comparison, Mek4 showed no significant transcription in the ES cell cultures by Northern analysis, whereas Eck displayed stronger signals in ES cells than in the embryoid bodies [4].
• Slap is found in a wide range of cell types and was shown to interact with the Eck receptor tyrosine kinase in a yeast two-hybrid interaction screen [1] [5].
• An enhancer element in the EphA2 (Eck) gene sufficient for rhombomere-specific expression is activated by HOXA1 and HOXB1 homeobox proteins [6].
• Both were found to be highly expressed in the developing lung and gut, while Eck was preferentially expressed in the thymus [7].

Biological context of Epha2

• This is the first description of a signal transduction pathway initiated by any member of the Eph/Eck family [8].
• Using the cytoplasmic domain of Eck as bait in a yeast two-hybrid screen of mouse embryonic and T-cell cDNA libraries, it was discovered that the p85 subunit of phosphatidylinositol 3-kinase bound Eck [8].
• In a search for additional receptor tyrosine kinases expressed during mouse embryogenesis we cloned the murine homolog of Eck, a member of the Eph subfamily, that maps to the distal region of mouse chromosome 4 [9].

Anatomical context of Epha2

• Before morphological segmentation, Sek-2 is transcribed in a transverse stripe corresponding to prospective r4 and the adjacent mesoderm, suggesting possible roles both in hindbrain segmentation and signalling between neuroepithelium and mesoderm [10].
• The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development [9].
• Taken together, our data suggest pleiotropic functions for the Eck receptor, initially in distinctive aspects of pattern formation and subsequently in development of several fetal tissues, and reveal possible allelism with known mouse developmental mutant loci [9].
• Germ-line inactivation of the murine Eck receptor tyrosine kinase by gene trap retroviral insertion [1].
• In hindbrain neuroepithelia, Eck protein localised specifically to cells of rhombomere 4 and was also seen transiently in cells populating second and third branchial arches and neurogenic facial crest VII-VIII and IX-X [9].

Associations of Epha2 with chemical compounds

• Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity [8].
• Further, using glutathione S-transferase fusion proteins, it was found that the C-terminal src homology 2 domain of the p85 subunit specifically interacted with Eck [8].
• Specific antisera defined Eck in murine embryonic cells as a glycoprotein of 130 kDa with an intrinsic autophosphorylation activity [9].

Regulatory relationships of Epha2

• 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 [7].

Other interactions of Epha2

• Characterization of B61, the ligand for the Eck receptor protein-tyrosine kinase [7].
• The extracellular domain of the Cek5 ligand shows a 27% sequence identity at the protein level to B61, a ligand for the related Eck RPTK (Bartley, T. D., et al. (1994) Nature 368, 558-560) [11].
• All the GPI-anchored ligands bind and activate one subclass of the Eph receptors (that represented by Eck) while the two transmembrane ligands bind and activate the other major subclass of receptors (represented by Elk) [12].
• This gene, designated hslap, appears to be the human ortholog of the recently described gene for the murine Src-like adaptor protein (mSLAP), a candidate intermediate in the signal-transduction pathway of the Eck receptor tyrosine kinase [13].
• During gastrulation, a high transient distribution of Eck was seen in mesodermal cells aggregating in the midline as notochordal plate [9].

Analytical, diagnostic and therapeutic context of Epha2

• In addition, the expression patterns of B61 and Eck during mouse ontogeny were determined by in situ hybridization [7].
• Immunohistochemical staining and laser scanning microscopy revealed a dynamic and tightly regulated distribution of Eck receptor protein in the developing mouse embryo [9].
• The eck(i) allele is essentially a null mutation since mutant mice are severely deficient for Eck protein as determined by Western blot analysis and in vitro kinase assays [1].

References