title: Filamins regulate cell spreading and initiation of cell migration.
abstract: Mammalian filamins (FLNs) are a family of three large actin-binding proteins. FLNa, the founding member of the family, was implicated in migration by cell biological analyses and the identification of FLNA mutations in the neuronal migration disorder periventricular heterotopia. However, recent knockout studies have questioned the relevance of FLNa to cell migration. Here we have used shRNA-mediated knockdown of FLNa, FLNb or FLNa and FLNb, or, alternatively, acute proteasomal degradation of all three FLNs, to generate FLN-deficient cells and assess their ability to migrate. We report that loss of FLNa or FLNb has little effect on migration but that knockdown of FLNa and FLNb, or proteolysis of all three FLNs, impairs migration. The observed defect is primarily a deficiency in initiation of motility rather than a problem with maintenance of locomotion speed. FLN-deficient cells are also impaired in spreading. Re-expression of full length FLNa, but not re-expression of a mutated FLNa lacking immunoglobulin domains 19 to 21, reverts both the spreading and the inhibition of initiation of migration.Our results establish a role for FLNs in cell migration and spreading and suggest that compensation by other FLNs may mask phenotypes in single knockout or knockdown cells. We propose that interactions between FLNs and transmembrane or signalling proteins, mediated at least in part by immunoglobulin domains 19 to 21 are important for both cell spreading and initiation of migration.
authors.affiliation: Department of Pharmacology and Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Baldassarre
authors.forename: Ziba
authors.initials: Z
authors.lastname: Razinia
authors.forename: Clara F
authors.initials: CF
authors.lastname: Burande
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lamsoul
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Lutz
authors.forename: David A
authors.initials: DA
authors.lastname: Calderwood
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003285:Contractile Proteins / Q000378:metabolism / Q000502:physiology*; D064448:Filamins; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D019169:Jurkat Cells; D008840:Microfilament Proteins / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D000199:Actins; D003285:Contractile Proteins; C578662:FLNB protein, human; D064448:Filamins; D007136:Immunoglobulins; D008840:Microfilament Proteins; D046988:Proteasome Endopeptidase Complex