title: Differential remodeling of actin cytoskeleton architecture by profilin isoforms leads to distinct effects on cell migration and invasion.
abstract: Dynamic actin cytoskeletal reorganization is integral to cell motility. Profilins are well-characterized regulators of actin polymerization; however, functional differences among coexpressed profilin isoforms are not well defined. Here, we demonstrate that profilin-1 and profilin-2 differentially regulate membrane protrusion, motility, and invasion; these processes are promoted by profilin-1 and suppressed by profilin-2. Compared to profilin-1, profilin-2 preferentially drives actin polymerization by the Ena/VASP protein, EVL. Profilin-2 and EVL suppress protrusive activity and cell motility by an actomyosin contractility-dependent mechanism. Importantly, EVL or profilin-2 downregulation enhances invasion in vitro and in vivo. In human breast cancer, lower EVL expression correlates with high invasiveness and poor patient outcome. We propose that profilin-2/EVL-mediated actin polymerization enhances actin bundling and suppresses breast cancer cell invasion.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Mouneimne
authors.forename: Scott D
authors.initials: SD
authors.lastname: Hansen
authors.forename: Laura M
authors.initials: LM
authors.lastname: Selfors
authors.forename: Lara
authors.initials: L
authors.lastname: Petrak
authors.forename: Michele M
authors.initials: MM
authors.lastname: Hickey
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Gallegos
authors.forename: Kaylene J
authors.initials: KJ
authors.lastname: Simpson
authors.forename: James
authors.initials: J
authors.lastname: Lim
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
authors.forename: R Dyche
authors.initials: RD
authors.lastname: Mullins
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009218:Myosins / Q000378:metabolism / Q000502:physiology; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051304:Profilins / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference
chemical_list: D015815:Cell Adhesion Molecules; C484449:EVL protein, human; D051304:Profilins; D020033:Protein Isoforms; D009218:Myosins