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

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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Figure 1: Abi1 binds to and activates N-WASP.
Figure 2: Abi1 is implicated in ruffle formation and macropinocytosis through WAVE, and vesicle rocketing and EGFR endocytosis through N-WASP.
Figure 3: Removal of Abi1 or N-WASP increases EGFR at the cell surface.
Figure 4: The overexpression of either N-WASP or Abi1 decreases cell-surface EGFR.
Figure 5: Removal of Abi1 or N-WASP increases TfR at the cell surface.

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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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Correspondence to Marie-France Carlier or Giorgio Scita.

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Innocenti, M., Gerboth, S., Rottner, K. et al. Abi1 regulates the activity of N-WASP and WAVE in distinct actin-based processes. Nat Cell Biol 7, 969–976 (2005). https://doi.org/10.1038/ncb1304

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