Unbalancing the phosphatidylinositol-4,5-bisphosphate-cofilin interaction impairs cell steering

Shirley Leyman, Mazen Sidani, Laila Ritsma, Davy Waterschoot, Robert Eddy, Daisy Dewitte, Olivier Debeir, Christine Decaestecker, Joël Vandekerckhove, Jacco Van Rheenen, Christophe Ampe, John Condeelis, Marleen Van Troys

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Cofilin is a key player in actin dynamics during cell migration. Its activity is regulated by (de)phosphorylation, pH, and binding to phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Here, we here use a human cofilin-1 (D122K) mutant with increased binding affinity for PI(4,5)P2 and slower release from the plasma membrane to study the role of the PI(4,5)P2-cofilin interaction in migrating cells. In fibroblasts in a background of endogenous cofilin, D122K cofilin expression negatively affects cell turning frequency. In carcinoma cells with down-regulated endogenous cofilin, D122K cofilin neither rescues the drastic morphological defects nor restores the effects in cell turning capacity, unlike what has been reported for wild-type cofilin. In cofilin knockdown cells, D122K cofilin expression promotes outgrowth of an existing lamellipod in response to epidermal growth factor (EGF) but does not result in initiation of new lamellipodia. This indicates that, next to phospho- and pH regulation, the normal release kinetics of cofilin from PI(4,5)P2 is crucial as a local activation switch for lamellipodia initiation and as a signal for migrating cells to change direction in response to external stimuli. Our results demonstrate that the PI(4,5)P2 regulatory mechanism, that is governed by EGF-dependent phospholipase C activation, is a determinant for the spatial and temporal control of cofilin activation required for lamellipodia initiation.

Original languageEnglish (US)
Pages (from-to)4509-4523
Number of pages15
JournalMolecular biology of the cell
Volume20
Issue number21
DOIs
StatePublished - Dec 1 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Leyman, S., Sidani, M., Ritsma, L., Waterschoot, D., Eddy, R., Dewitte, D., Debeir, O., Decaestecker, C., Vandekerckhove, J., Van Rheenen, J., Ampe, C., Condeelis, J., & Van Troys, M. (2009). Unbalancing the phosphatidylinositol-4,5-bisphosphate-cofilin interaction impairs cell steering. Molecular biology of the cell, 20(21), 4509-4523. https://doi.org/10.1091/mbc.E09-02-0121