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CDC42 switches IRSp53 from inhibition of actin growth to elongation by clustering of VASP

Andrea Disanza, Sara Bisi, Moritz Winterhoff, Francesca Milanesi, Dmitry S Ushakov, David Kast, Paola Marighetti, Guillaume Romet‐Lemonne, Hans‐Michael Müller, Walter Nickel, Joern Linkner, Davy Waterschoot, Christophe Ampè, Salvatore Cortellino, Andrea Palamidessi, Roberto Dominguez, Marie‐France Carlier, Jan Faix, Giorgio Scita

Author Affiliations

  1. Andrea Disanza1,,
  2. Sara Bisi1,,
  3. Moritz Winterhoff2,
  4. Francesca Milanesi1,,
  5. Dmitry S Ushakov2,§,
  6. David Kast3,
  7. Paola Marighetti1,
  8. Guillaume Romet‐Lemonne4,
  9. Hans‐Michael Müller5,
  10. Walter Nickel5,
  11. Joern Linkner2,
  12. Davy Waterschoot6,
  13. Christophe Ampè6,
  14. Salvatore Cortellino1,
  15. Andrea Palamidessi1,
  16. Roberto Dominguez3,
  17. Marie‐France Carlier4,
  18. Jan Faix*,2 and
  19. Giorgio Scita*,1,7
  1. 1 IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
  2. 2 Hannover Medical School, Institute for Biophysical Chemistry, Hannover, Germany
  3. 3 Department of Physiology, Perelman School of Medicine Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
  4. 4 Cytoskeleton Dynamics and Motility Group, Laboratoire d'Enzymologie et Biochimie Structurales, Centre de Recherche de Gif, CNRS, Gif‐sur‐Yvette, France
  5. 5 Heidelberg University Biochemistry Center, Heidelberg, Germany
  6. 6 Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
  7. 7 Dipartimento di Scienze della Salute, Universita’ degli Studi di Milano, Milan, Italy
  1. *Corresponding authors. Hannover Medical School, Institute for Biophysical Chemistry, OE 4350, Carl‐Neuberg‐Str. 1, D‐30625 Hannover, Germany. Tel.:+49 511 532 2928; Fax:+49 511 532 5966; E-mail: faix.jan{at}mh-hannover.deDipartimento di Scienze della Salute, Universita’ degli Studi di Milano, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, via Adamello, 16, Milan 20141, Italy. Tel.:+39 02574303277; Fax:+39 02574303231; E-mail: giorgio.scita{at}ifom.eu
  1. These authors contributed equally to this work

  • Present address: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, at the IFOM‐IEO Campus, Milan, Italy

  • § Present address: Faculty of Biological Sciences, University of Leeds, Leeds, UK

Abstract

Filopodia explore the environment, sensing soluble and mechanical cues during directional motility and tissue morphogenesis. How filopodia are initiated and spatially restricted to specific sites on the plasma membrane is still unclear. Here, we show that the membrane deforming and curvature sensing IRSp53 (Insulin Receptor Substrate of 53 kDa) protein slows down actin filament barbed end growth. This inhibition is relieved by CDC42 and counteracted by VASP, which also binds to IRSp53. The VASP:IRSp53 interaction is regulated by activated CDC42 and promotes high‐density clustering of VASP, which is required for processive actin filament elongation. The interaction also mediates VASP recruitment to liposomes. In cells, IRSp53 and VASP accumulate at discrete foci at the leading edge, where filopodia are initiated. Genetic removal of IRSp53 impairs the formation of VASP foci, filopodia and chemotactic motility, while IRSp53 null mice display defective wound healing. Thus, IRSp53 dampens barbed end growth. CDC42 activation inhibits this activity and promotes IRSp53‐dependent recruitment and clustering of VASP to drive actin assembly. These events result in spatial restriction of VASP filament elongation for initiation of filopodia during cell migration, invasion, and tissue repair.

  • Received March 22, 2013.
  • Accepted August 30, 2013.

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