Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex

Andrea Disanza, Sara Mantoani, Maud Hertzog, Silke Gerboth, Emanuela Frittoli, Anika Steffen, Kerstin Berhoerster, Hans Juergen Kreienkamp, Francesca Milanesi, Pier Paolo Di Fiore, Andrea Ciliberto, Theresia E B Stradal, Giorgio Scita

Research output: Contribution to journalArticle

Abstract

Actin-crosslinking proteins organize actin into highly dynamic and architecturally diverse subcellular scaffolds that orchestrate a variety of mechanical processes, including lamellipodial and filopodial protrusions in motile cells. How signalling pathways control and coordinate the activity of these crosslinkers is poorly defined. IRSp53, a multi-domain protein that can associate with the Rho-GTPases Rac and Cdc42, participates in these processes mainly through its amino-terminal IMD (IRSp53 and MIM domain). The isolated IMD has actin-bundling activity in vitro and is sufficient to induce filopodia in vivo. However, the manner of regulation of this activity in the full-length protein remains largely unknown. Eps8 is involved in actin dynamics through its actin barbed-ends capping activity and its ability to modulate Rac activity. Moreover, Eps8 binds to IRSp53. Here, we describe a novel actin crosslinking activity of Eps8. Additionally, Eps8 activates and synergizes with IRSp53 in mediating actin bundling in vitro, enhancing IRSp53-dependent membrane extensions in vivo. Cdc42 binds to and controls the cellular distribution of the IRSp53-Eps8 complex, supporting the existence of a Cdc42-IRSp53-Eps8 signalling pathway. Consistently, Cdc42-induced filopodia are inhibited following individual removal of either IRSp53 or Eps8. Collectively, these results support a model whereby the synergic bundling activity of the IRSp53-Eps8 complex, regulated by Cdc42, contributes to the generation of actin bundles, thus promoting filopodial protrusions.

Original languageEnglish
Pages (from-to)1337-1347
Number of pages11
JournalNature Cell Biology
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 2006

ASJC Scopus subject areas

  • Cell Biology

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    Disanza, A., Mantoani, S., Hertzog, M., Gerboth, S., Frittoli, E., Steffen, A., Berhoerster, K., Kreienkamp, H. J., Milanesi, F., Di Fiore, P. P., Ciliberto, A., Stradal, T. E. B., & Scita, G. (2006). Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. Nature Cell Biology, 8(12), 1337-1347. https://doi.org/10.1038/ncb1502