Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion.
Eph tyrosine kinase receptors and their membrane-bound ligands, ephrins, are presumed to regulate cell-cell interactions. The major consequence of bidirectional activation of Eph receptors and ephrin ligands is cell repulsion. In this study, we discovered that Xenopus Dishevelled (Xdsh) forms a complex with Eph receptors and ephrin-B ligands and mediates the cell repulsion induced by Eph and ephrin. In vitro re-aggregation assays with Xenopus animal cap explants revealed that co-expression of a dominant-negative mutant of Xdsh affected the sorting of cells expressing EphB2 and those expressing ephrin-B1. Co-expression of Xdsh induced the activation of RhoA and Rho kinase in the EphB2-overexpressed cells and in the cells expressing EphB2-stimulated ephrin-B1. Therefore, Xdsh mediates both forward and reverse signaling of EphB2 and ephrin-B1, leading to the activation of RhoA and its effector protein Rho kinase. The inhibition of RhoA activity in animal caps significantly prevents the EphB2- and ephrin-B1-mediated cell sorting. We propose that Xdsh, which is expressed in various tissues, is involved in EphB and ephrin-B signaling related to regulation of cell repulsion via modification of RhoA activity.
Tanaka
Masamitsu
M
First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
Kamo
Takaharu
T
Ota
Satoshi
S
Sugimura
Haruhiko
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000072261:Dishevelled Proteins; D036342:Ephrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism*; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D036342:Ephrins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D029867:Xenopus Proteins; D036081:Receptors, Eph Family; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein