Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Pré-Publication, Document De Travail Année : 2022

Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration

Anna Polesskaya
Arthur Boutillon
  • Fonction : Auteur
Sheng Yang
  • Fonction : Auteur
Yanan Wang
  • Fonction : Auteur
Stéphane Romero
  • Fonction : Auteur
Yijun Liu
  • Fonction : Auteur
Marc Lavielle
  • Fonction : Auteur
Nicolas Molinie
  • Fonction : Auteur
Nathalie Rocques
  • Fonction : Auteur
Artem Fokin
Raphaël Guérois
  • Fonction : Auteur
Baoyu Chen
  • Fonction : Auteur
Nicolas David
Alexis Gautreau

Résumé

Abstract Branched actin networks polymerized by the Arp2/3 complex are critical for cell migration. The WAVE complex is the machinery that activates Arp2/3 in a RAC1-dependent manner at the leading edge of migrating cells. Multiple WAVE complexes are assembled in a cell through various combinations of paralogous subunits. Here we report the surprising phenotype associated with loss-of-function of CYFIP2, a subunit of the WAVE complex. In three different human mammary cell lines and in prechordal plate cells of gastrulating zebrafish embryos, CYFIP2 depletion promoted, rather than impaired, membrane protrusions and migration persistence. CYFIP2, however, assembled WAVE complexes that polymerize branched actin at the cell cortex and rescued membrane protrusions of CYFIP1/2 double knock-out cells, although less efficiently than CYFIP1. Point mutations of CYFIP2 associated with intellectual disability in children were gain-of-function, as they made CYFIP2 as active as CYFIP1 in this rescue experiment. Biochemical reconstitutions of CYFIP2-containing WAVE complexes showed that they bound equally well to active RAC1 as CYFIP1-containing WAVE complexes, yet they were poorly activated in response to RAC1 binding. Together these results suggest that CYFIP2-containing WAVE complexes titrate active RAC1 and thereby prevent efficient CYFIP1-containing complexes from being activated. In this context, where cell migration is governed by the balance of CYFIP1/2 expression, releasing the restrained activity of CYFIP2-containing WAVE complexes leads to pathology.

Dates et versions

hal-03823496 , version 1 (21-10-2022)

Identifiants

Citer

Anna Polesskaya, Arthur Boutillon, Sheng Yang, Yanan Wang, Stéphane Romero, et al.. Restrained activation of CYFIP2-containing WAVE complexes controls membrane protrusions and cell migration. 2022. ⟨hal-03823496⟩

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