Letter | Published:

Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes

Nature Cell Biology volume 7, pages 969976 (2005) | Download Citation

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Abstract

Neural Wiskott–Aldrich syndrome protein (N-WASP) and WAVE are members of a family of proteins that use the Arp2/3 complex to stimulate actin assembly in actin-based motile processes. By entering into distinct macromolecular complexes, they act as convergent nodes of different signalling pathways. The role of WAVE in generating lamellipodial protrusion during cell migration is well established. Conversely, the precise cellular functions of N-WASP have remained elusive. Here, we report that Abi1, an essential component of the WAVE protein complex, also has a critical role in regulating N-WASP-dependent function. Consistently, Abi1 binds to N-WASP with nanomolar affinity and, cooperating with Cdc42, potently induces N-WASP activity in vitro. Molecular genetic approaches demonstrate that Abi1 and WAVE, but not N-WASP, are essential for Rac-dependent membrane protrusion and macropinocytosis. Conversely, Abi1 and N-WASP, but not WAVE, regulate actin-based vesicular transport, epidermal growth factor receptor (EGFR) endocytosis, and EGFR and transferrin receptor (TfR) cell-surface distribution. Thus, Abi1 is a dual regulator of WAVE and N-WASP activities in specific processes that are dependent on actin dynamics.

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Acknowledgements

This work was supported by grants from: Associazione Italiana Ricerca sul Cancro (AIRC) and AIRC Regionale Lombardia to G.S.; Human Science Frontier Program to G.S. and M.F.C. (grant number RGP0072/2003-C); the Italian Ministry of Health (grant R.F. 02/184) to G.S.; the French Ligue Nationale Contre le Cancer to M.F.C. ('équipe labellisée Ligue'); the Fondazione Italiana Ricerca sul Cancro (FIRC) to M.I.; European Community (VI Framework) to G.S.; EMBO to M.H.; and from the Deutsche Forschungsgemeinschaft (DFG) (SPP 1150) to K.R. and T.E.B.S. We would like to thank M. Garre and S. Bossi for technical help, and S. Lommel for providing N-WASP constructs.

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Affiliations

  1. IFOM, Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20134, Milan, Italy.

    • Metello Innocenti
    • , Silke Gerboth
    • , Maud Hertzog
    • , Emanuela Frittoli
    • , Simona Polo
    • , Andrea Disanza
    • , Pier Paolo Di Fiore
    •  & Giorgio Scita
  2. Department of Experimental Oncology, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141, Milan, Italy.

    • Metello Innocenti
    • , Silke Gerboth
    • , Maud Hertzog
    • , Emanuela Frittoli
    • , Simona Polo
    • , Andrea Disanza
    • , Pier Paolo Di Fiore
    •  & Giorgio Scita
  3. Cytoskeleton Dynamics Group, German Research Centre for Biotechnology (GBF), Mascheroder Weg 1, D-38124 Braunschweig, Germany.

    • Klemens Rottner
    • , Frank P. L. Lai
    •  & Stefanie Benesch
  4. Signalling and Motility Group, German Research Centre for Biotechnology (GBF), Mascheroder Weg 1, D-38124 Braunschweig, Germany.

    • Theresia E. B. Stradal
  5. Dynamique du Cytosquelette Laboratoire d'Enzymologie et Biochimie Structurales, C.N.R.S. 91198 Gif-sur-Yvette, France.

    • Maud Hertzog
    • , Dominique Didry
    •  & Marie-France Carlier
  6. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, 20122 Milan, Italy.

    • Pier Paolo Di Fiore

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The authors declare no competing financial interests.

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Correspondence to Marie-France Carlier or Giorgio Scita.

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DOI

https://doi.org/10.1038/ncb1304

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