Nature Cell Biology
- 8, 1337 - 1347 (2006)
Published online: 19 November 2006; | doi:10.1038/ncb1502
Regulation of cell shape by Cdc42 is mediated by the synergic actin-bundling activity of the Eps8–IRSp53 complexAndrea Disanza1, 2, 6, 7, Sara Mantoani1, 2, 7, Maud Hertzog1, 2, 7, Silke Gerboth1, 2, Emanuela Frittoli1, 2, Anika Steffen1, 2, 4, Kerstin Berhoerster5, Hans-Juergen Kreienkamp5, Francesca Milanesi1, 2, Pier Paolo Di Fiore1, 2, 6, Andrea Ciliberto1, 2, Theresia E. B. Stradal4 & Giorgio Scita1, 21
Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139, Milan, Italy. 2
Department of Experimental Oncology, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141, Milan, Italy. 4
Signalling and Motility Group, German Research Centre for Biotechnology (GBF), Mascheroder Weg 1, D-38124 Braunschweig, Germany. 5
Institute for Human Genetics, University Hospital Eppendorf, Hamburg Martinistrasse 52, D-20246 Hamburg, Germany. 6
Dipartimento di Medicina, Chirurgia ed Odonoiatria, Università degli Studi di Milano, 20122 Milan, Italy. 7
These authors contributed equally to this work.
Correspondence should be addressed to Giorgio Scita giorgio.scita@ifom-ieo-campus.it 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.
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