Ephrins are transmembrane ligands for transmembrane receptors that mediate cell adhesion signaling. Interaction of the tethered ligand with the receptor initiates signaling cascades in both the ligand-expressing cell (reverse signaling) and the receptor-expressing cell (forward signaling). Lu et al. identified a protein (PDZ-RGS3) with a PDZ domain and regulator of G protein-signaling (RGS) activity as a partner for the cytoplasmic domain of ephrin B. These two proteins were expressed in similar regions of the mouse embryos and could be coprecipitated from mouse cortex, suggesting that these proteins interact in vivo. In Xenopus embryo de-adhesion assays, microinjection of ephrin B1 mRNA led to de-adhesion. Interaction of ephrin B1 with the PDZ domain of PDZ-RGS3 was essential for this ephrin activity and the de-adhesion activity could be blocked by coexpression of an RGS-deficient mutant of the PDZ-RGS3 protein. Ephrin B1 inhibited migration of cerebellar granule cells in culture in response to the chemokine SDF-1, which activates a G protein-coupled receptor. Thus, reverse signaling by ephrin B1 mediated by interactions with PDZ-RGS3 represents a mechanism by which the ephrin pathway can modify G protein-coupled receptor signaling cascades.
Q. Lu, E. E. Sun, R. S. Klein, J. G. Flanagan, Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105, 69-79 (2001). [Online Journal]