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

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...

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Main Authors: Disanza, Andrea (Author) , Bisi, Sara (Author) , Winterhoff, Moritz (Author) , Milanesi, Francesca (Author) , Ushakov, Dmitry S (Author) , Kast, David (Author) , Marighetti, Paola (Author) , Romet-Lemonne, Guillaume (Author) , Müller, Hans-Michael (Author) , Nickel, Walter (Author) , Linkner, Joern (Author) , Waterschoot, Davy (Author) , Ampè, Christophe (Author) , Cortellino, Salvatore (Author) , Palamidessi, Andrea (Author) , Dominguez, Roberto (Author) , Carlier, Marie-France (Author) , Faix, Jan (Author) , Scita, Giorgio (Author)
Format: Article (Journal)
Language:English
Published: 27 September 2013
In: The EMBO journal
Year: 2013, Volume: 32, Issue: 20, Pages: 2735-2750
ISSN:1460-2075
DOI:10.1038/emboj.2013.208
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/emboj.2013.208
Verlag, lizenzpflichtig, Volltext: https://www.embopress.org/doi/full/10.1038/emboj.2013.208
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Author Notes: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 and Giorgio Scita
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Summary: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.
Item Description:Gesehen am 17.12.2020
Physical Description:Online Resource
ISSN:1460-2075
DOI:10.1038/emboj.2013.208

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