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

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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

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Cell Shape
Actins
Pseudopodia
Mechanical Phenomena
rho GTP-Binding Proteins
Proteins
Membranes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Disanza, A., Mantoani, S., Hertzog, M., Gerboth, S., Frittoli, E., Steffen, A., ... 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

Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. / Disanza, Andrea; Mantoani, Sara; Hertzog, Maud; Gerboth, Silke; Frittoli, Emanuela; Steffen, Anika; Berhoerster, Kerstin; Kreienkamp, Hans Juergen; Milanesi, Francesca; Di Fiore, Pier Paolo; Ciliberto, Andrea; Stradal, Theresia E B; Scita, Giorgio.

In: Nature Cell Biology, Vol. 8, No. 12, 12.2006, p. 1337-1347.

Research output: Contribution to journalArticle

Disanza, A, Mantoani, S, Hertzog, M, Gerboth, S, Frittoli, E, Steffen, A, Berhoerster, K, Kreienkamp, HJ, Milanesi, F, Di Fiore, PP, Ciliberto, A, Stradal, TEB & 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, vol. 8, no. 12, pp. 1337-1347. https://doi.org/10.1038/ncb1502
Disanza, Andrea ; Mantoani, Sara ; Hertzog, Maud ; Gerboth, Silke ; Frittoli, Emanuela ; Steffen, Anika ; Berhoerster, Kerstin ; Kreienkamp, Hans Juergen ; Milanesi, Francesca ; Di Fiore, Pier Paolo ; Ciliberto, Andrea ; Stradal, Theresia E B ; Scita, Giorgio. / Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8-IRSp53 complex. In: Nature Cell Biology. 2006 ; Vol. 8, No. 12. pp. 1337-1347.
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