Dok-R plays a pivotal role in angiopoietin-1-dependent cell migration through recruitment and activation of Pak

Tek/Tie-2 is an endothelial cell (EC)-specific receptor tyrosine kinase tha t plays a critical role in angiogenesis via its regulation by the angiopoie tin family of growth factor ligands. Angiopoietin-1 (Ang1) can promote EC m igration; however, the signaling mechanisms underlying this process remain elusive. Here we demonstrate that Dok-R/Dok-2 can associate with Tek in ECs following Ang1 stimulation, resulting in tyrosine phosphorylation of Dok-R and the subsequent recruitment of Nck and the p21-activating kinase (Pak/P ak1) to the activated receptor. Ang1-mediated migration is increased upon D ok-R overexpression and this requires a functional Nck binding site on Dok- R. Localization of this Dok-R-Nck-Pak complex to the activated Tek receptor at the cellular membrane is coincident with activation of Pak kinase. The ability of Dok-R to bind Nck is required for maximal activation of Pak and overexpression of Pak results in increased Ang1-mediated cell motility. Our study outlines a novel signaling pathway underlying Ang1-driven cell migra tion that involves Dok-R and its recruitment of Nck and the subsequent acti vation of Pak.