title: Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1-induced collective directional migration and angiogenic sprouting.
abstract: Angiogenic sprouting requires that cell-cell contacts be maintained during migration of endothelial cells. Angiopoietin-1 (Ang-1) and vascular endothelial growth factor act oppositely on endothelial cell junctions. We found that Ang-1 promotes collective and directional migration and, in contrast to VEGF, induces the formation of a complex formed of atypical protein kinase C (PKC)-ζ and β-catenin at cell-cell junctions and at the leading edge of migrating endothelial cells. This complex brings Par3, Par6, and adherens junction proteins at the front of migrating cells to locally activate Rac1 in response to Ang-1. The colocalization of PKCζ and β-catenin at leading edge along with PKCζ-dependent stabilization of cell-cell contacts promotes directed and collective endothelial cell migration. Consistent with these results, down-regulation of PKCζ in endothelial cells alters Ang-1-induced sprouting in vitro and knockdown in developing zebrafish results in intersegmental vessel defects caused by a perturbed directionality of tip cells and by loss of cell contacts between tip and stalk cells. These results reveal that PKCζ and β-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis.
authors.affiliation: Laboratory of Endothelial Cell Biology, Institut de recherches cliniques de Montréal, Université de Montréal, QC, Canada.
authors.forename: Malika
authors.initials: M
authors.lastname: Oubaha
authors.forename: Michelle I
authors.initials: MI
authors.lastname: Lin
authors.forename: Yoran
authors.initials: Y
authors.lastname: Margaron
authors.forename: Dominic
authors.initials: D
authors.lastname: Filion
authors.forename: Emily N
authors.initials: EN
authors.lastname: Price
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gratton
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D042683:Angiopoietin-1 / Q000494:pharmacology*; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D016764:Cell Polarity; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D007365:Intercellular Junctions / Q000378:metabolism; D008845:Microinjections; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D014945:Wound Healing; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D042683:Angiopoietin-1; D011493:Protein Kinase C; D051176:beta Catenin; D000099221:Protein Kinase C zeta