The WASP–WAVE protein network: connecting the membrane to the cytoskeleton

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Abstract
Wiskott–Aldrich syndrome protein (WASP) and WASP-family verprolin-homologous protein (WAVE) family proteins activate the ARP2/3 complex to promote reorganization of the actin cytoskeleton. The N-terminal domain of the WASP and WAVE proteins contributes to stable protein–protein interactions, thereby contributing to the formation of the protein complex. Intramolecular interaction suppresses the ARP2/3-complex-activating capability of WASP and neural (N-)WASP. The role of intramolecular or intermolecular interactions in the regulation of WAVE proteins is still unclear. Phosphatidylinositol phosphates bind to WASP and WAVE proteins and contribute to the localization of these proteins, and they also regulate their capability to activate the ARP2/3 complex. Many proteins with Src-homology-3 (SH3) domains bind to the proline-rich region of WASP and WAVE proteins, and enhance the ARP2/3 activation of WASP and WAVE. Most of the proteins with SH3 domains are adaptors that link WASP and WAVE proteins to other proteins or the cell membrane. The Bin, amphiphysin, Rvs167 (BAR) and extended Fer-CIP4 homology (EFC) domains are membrane-binding and membrane-deforming domains. Most BAR- or EFC-domain-containing proteins have SH3 domains that bind to N-WASP, and are involved in endocytosis. The Rac binding (RCB, also known as the IRSp53-Mim-homology domain (IMD)) domain of IRSp53 shares structural similarity to the BAR domain and binds to the membrane. IRSp53 binds to WAVE2 for lamellipodium formation. WASP and N-WASP are involved in cell-shape changes that occur inwardly (endocytosis) and outwardly (filopodia and podosomes). WAVE proteins are involved in outward (lamellipodia) cell-shape changes only. Membrane deformation might be coupled to WASP- and WAVE-mediated cytoskeletal changes.