title: Cortactin activation by FVIIa/tissue factor and PAR2 promotes endothelial cell migration.
abstract: Cellular migration is a complex process that requires the polymerization of actin filaments to drive cellular extension. Smooth muscle and cancer cell migration has been shown to be affected by coagulation factors, notably the factor VII (FVIIa) and tissue factor (TF) complex. The present studies delineated mediators involved with the process of FVIIa/TF-induced cell migration and utilized a simple, precise, and reproducible, migration assay. Both FVIIa and protease-activated receptor-2 (PAR2)-activating peptide, SLIGRL, increased the migration rate of porcine cerebral microvascular endothelial cells (pCMVECs) overexpressing human TF. Ras homolog gene family member A (RhoA) and cortactin were upregulated during the process; expression of HIF, actin polymerization nuclear diaphanous-related formin-1 and -2 (Dia1, and Dia2) were unaffected. Gene silencing by shRNA to PAR2, RhoA, and cortactin attenuated this gene upregulation and migration induced by FVIIa/TF. Utilizing immunocellular localization, we demonstrate that during FVIIa/TF and PAR2 activation, cortactin molecules translocate from the cytoplasm to the cell periphery and assist in lamellipodia formation of pCMVECs. Overall, we demonstrate a novel regulation and role for cortactin in FVIIa/TF-mediated endothelial cell migration that occurs through a PAR2 and RhoA dependent mechanism.
authors.affiliation: Department of Pediatrics, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Quebec, Canada.
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Mancini
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Martin
authors.initials: M
authors.lastname: Leduc
authors.forename: Karine
authors.initials: K
authors.lastname: Zaniolo
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Xin
authors.initials: X
authors.lastname: Hou
authors.forename: Georges-Etienne
authors.initials: GE
authors.lastname: Rivard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015942:Factor VIIa / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic; D009842:Oligopeptides / Q000494:pharmacology; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013552:Swine; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051356:Cortactin; D009842:Oligopeptides; D044464:Receptor, PAR-2; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D013925:Thromboplastin; D015942:Factor VIIa; D020742:rhoA GTP-Binding Protein