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

Zubin Master, Nina Jones, Jennifer Tran, Jamie Jones, Robert S. Kerbel, Daniel J. Dumont

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5919-5928
Number of pages10
JournalEMBO Journal
Volume20
Issue number21
DOIs
StatePublished - Nov 1 2001

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Keywords

  • Angiogenesis
  • Angiopoietin
  • Dok
  • Migration
  • Tek/Tie-2

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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