title: Macrophage mesenchymal migration requires podosome stabilization by filamin A.
abstract: Filamin A (FLNa) is a cross-linker of actin filaments and serves as a scaffold protein mostly involved in the regulation of actin polymerization. It is distributed ubiquitously, and null mutations have strong consequences on embryonic development in humans, with organ defects which suggest deficiencies in cell migration. We have reported previously that macrophages, the archetypal migratory cells, use the protease- and podosome-dependent mesenchymal migration mode in dense three-dimensional environments, whereas they use the protease- and podosome-independent amoeboid mode in more porous matrices. Because FLNa has been shown to localize to podosomes, we hypothesized that the defects seen in patients carrying FLNa mutations could be related to the capacity of certain cell types to form podosomes. Using strategies based on FLNa knock-out, knockdown, and rescue, we show that FLNa (i) is involved in podosome stability and their organization as rosettes and three-dimensional podosomes, (ii) regulates the proteolysis of the matrix mediated by podosomes in macrophages, (iii) is required for podosome rosette formation triggered by Hck, and (iv) is necessary for mesenchymal migration but dispensable for amoeboid migration. These new functions assigned to FLNa, particularly its role in mesenchymal migration, could be directly related to the defects in cell migration described during the embryonic development in FLNa-defective patients.
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS), Unité Mixte de Recherche 5089, 205 route de Narbonne, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guiet
authors.forename: Christel
authors.initials: C
authors.lastname: Vérollet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamsoul
authors.forename: Céline
authors.initials: C
authors.lastname: Cougoule
authors.forename: Renaud
authors.initials: R
authors.lastname: Poincloux
authors.forename: Arnaud
authors.initials: A
authors.lastname: Labrousse
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
authors.forename: Michael
authors.initials: M
authors.lastname: Glogauer
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Lutz
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maridonneau-Parini
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D064448:Filamins; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D051572:Proto-Oncogene Proteins c-hck / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck