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.
Master
Z
Z
Division of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Research Building, S-wing, Room 227, Toronto, Ontario, M4N 3M5, Canada.
Jones
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N
Tran
J
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Jones
J
J
Kerbel
R S
RS
Dumont
D J
DJ
D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1; D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054462:p21-Activated Kinases
D048868:Adaptor Proteins, Signal Transducing; D042683:Angiopoietin-1; D002352:Carrier Proteins; C115089:DOK2 protein, human; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; C078332:Nck protein; D015513:Oncogene Proteins; D010750:Phosphoproteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C515903:PAK1 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases