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

EMBO J. 2001 Nov 1;20(21):5919-28. doi: 10.1093/emboj/20.21.5919.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Angiopoietin-1
  • Binding Sites / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Humans
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / metabolism
  • Macromolecular Substances
  • Membrane Glycoproteins / pharmacology*
  • Oncogene Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Binding / physiology
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor, TIE-2
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • p21-Activated Kinases

Substances

  • Adaptor Proteins, Signal Transducing
  • Angiopoietin-1
  • Carrier Proteins
  • DOK2 protein, human
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Nck protein
  • Oncogene Proteins
  • Phosphoproteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, TIE-2
  • PAK1 protein, human
  • Protein Serine-Threonine Kinases
  • p21-Activated Kinases