title: Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA.
abstract: The actin and intermediate filament cytoskeletons contribute to numerous cellular processes, including morphogenesis, cytokinesis and migration. These two cytoskeletal systems associate with each other, but the underlying mechanisms of this interaction are incompletely understood. Here, we show that inactivation of vimentin leads to increased actin stress fiber assembly and contractility, and consequent elevation of myosin light chain phosphorylation and stabilization of tropomyosin-4.2 (see Geeves et al., 2015). The vimentin-knockout phenotypes can be rescued by re-expression of wild-type vimentin, but not by the non-filamentous 'unit length form' vimentin, demonstrating that intact vimentin intermediate filaments are required to facilitate the effects on the actin cytoskeleton. Finally, we provide evidence that the effects of vimentin on stress fibers are mediated by activation of RhoA through its guanine nucleotide exchange factor GEF-H1 (also known as ARHGEF2). Vimentin depletion induces phosphorylation of the microtubule-associated GEF-H1 on Ser886, and thereby promotes RhoA activity and actin stress fiber assembly. Taken together, these data reveal a new mechanism by which intermediate filaments regulate contractile actomyosin bundles, and may explain why elevated vimentin expression levels correlate with increased migration and invasion of cancer cells.
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, Helsinki 00014, Finland yaming.jiu@helsinki.fi pekka.lappalainen@helsinki.fi.
authors.forename: Yaming
authors.identifier: 0000-0002-8601-8820
authors.initials: Y
authors.lastname: Jiu
authors.affiliation: Faculty of Medicine, P.O. Box 63, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Johan
authors.initials: J
authors.lastname: Peränen
authors.affiliation: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Niccole
authors.initials: N
authors.lastname: Schaible
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FI-20521 Turku, Finland.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, FI-20520 Turku, Finland.|Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FI-20521 Turku, Finland.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.affiliation: Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Krishnan
authors.affiliation: Institute of Biotechnology, P.O. Box 56, University of Helsinki, Helsinki 00014, Finland yaming.jiu@helsinki.fi pekka.lappalainen@helsinki.fi.
authors.forename: Pekka
authors.identifier: 0000-0001-6227-0354
authors.initials: P
authors.lastname: Lappalainen
mesh_terms: D000199:Actins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism*; D010766:Phosphorylation; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D022502:Stress Fibers / Q000378:metabolism*; D014746:Vimentin / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; D000199:Actins; D064067:Rho Guanine Nucleotide Exchange Factors; D014746:Vimentin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein
keywords: Actin; GEF-H1; Intermediate filament; RhoA; Stress fiber; Vimentin