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 that plays a critical role in angiogenesis via its regulation by the angiopoietin family of growth factor ligands. Angiopoietin‐1 (Ang1) can promote EC migration; 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/Pak1) to the activated receptor. Ang1‐mediated migration is increased upon Dok‐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 migration that involves Dok‐R and its recruitment of Nck and the subsequent activation of Pak.