title: Rho/ROCK pathway inhibition by the CDK inhibitor p27(kip1) participates in the onset of macrophage 3D-mesenchymal migration.
abstract: Infiltration of macrophages into tissue can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid migration--common to all leukocytes, and mesenchymal migration--restricted to macrophages and certain tumour cells. Here, we investigate the initiating mechanisms involved in macrophage mesenchymal migration. We show that a single macrophage is able to use both migration modes. Macrophage mesenchymal migration is correlated with decreased activity of Rho/Rho-associated protein kinase (ROCK) and is potentiated when ROCK is inhibited, suggesting that amoeboid inhibition participates in mechanisms that initiate mesenchymal migration. We identify the cyclin-dependent kinase (CDK) inhibitor p27(kip1) (also known as CDKN1B) as a new effector of macrophage 3D-migration. By using p27(kip1) mutant mice and small interfering RNA targeting p27(kip1), we show that p27(kip1) promotes mesenchymal migration and hinders amoeboid migration upstream of the Rho/ROCK pathway, a process associated with a relocation of the protein from the nucleus to the cytoplasm. Finally, we observe that cytoplasmic p27(kip1) is required for in vivo infiltration of macrophages within induced tumours in mice. This study provides the first evidence that silencing of amoeboid migration through inhibition of the Rho/ROCK pathway by p27(kip1) participates in the onset of macrophage mesenchymal migration.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP64182, F-31077 Toulouse, France Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gui
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP64182, F-31077 Toulouse, France Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Labrousse
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP64182, F-31077 Toulouse, France Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Van Goethem
authors.affiliation: INSERM UMR1037-Cancer Research Center of Toulouse, Université de Toulouse, CNRS ERL5294, Toulouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besson
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP64182, F-31077 Toulouse, France Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France isabelle.maridonneau-parini@ipbs.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, BP64182, F-31077 Toulouse, France Université de Toulouse, UPS, IPBS, F-31077 Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Le Cabec
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins
keywords: 3D-migration; Amoeboid; CDKN1B; Macrophage; Mesenchymal; Rho/ROCK pathway; p27kip1