title: CARMIL2 is a novel molecular connection between vimentin and actin essential for cell migration and invadopodia formation.
abstract: Cancer cell migration requires the regulation of actin networks at protrusions associated with invadopodia and other leading edges. Carcinomas become invasive after undergoing an epithelial-mesenchymal transition characterized by the appearance of vimentin filaments. While vimentin expression correlates with cell migration, the molecular connections between vimentin- and actin-based membrane protrusions are not understood. We report here that CARMIL2 (capping protein, Arp2/3, myosin-I linker 2) provides such a molecular link. CARMIL2 localizes to vimentin, regulates actin capping protein (CP), and binds to membranes. CARMIL2 is necessary for invadopodia formation, as well as cell polarity, lamellipodial assembly, membrane ruffling, macropinocytosis, and collective cell migration. Using point mutants and chimeras with defined biochemical and cellular properties, we discovered that localization to vimentin and CP binding are both essential for the function of CARMIL2 in cells. On the basis of these results, we propose a model in which dynamic vimentin filaments target CARMIL2 to critical membrane-associated locations, where CARMIL2 regulates CP, and thus actin assembly, to create cell protrusions.
authors.affiliation: Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: M Hunter
authors.initials: MH
authors.lastname: Lanier
authors.affiliation: Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63110.
authors.forename: Taekyung
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO 63110 jacooper@wustl.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Cooper
mesh_terms: D051344:Actin Capping Proteins / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D022081:Cell Surface Extensions / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007382:Intermediate Filaments / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D000069261:Podosomes / Q000235:genetics / Q000473:pathology; D014746:Vimentin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051344:Actin Capping Proteins; D000199:Actins; C547525:CARMIL1 protein, human; D008840:Microfilament Proteins; D014746:Vimentin