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

Nature Reviews Molecular Cell Biology volume 8, pages 37–48 (2007)Cite this article

Key Points

  • 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.

Abstract

Wiskott–Aldrich syndrome protein (WASP) and WASP-family verprolin-homologous protein (WAVE) family proteins are scaffolds that link upstream signals to the activation of the ARP2/3 complex, leading to a burst of actin polymerization. ARP2/3-complex-mediated actin polymerization is crucial for the reorganization of the actin cytoskeleton at the cell cortex for processes such as cell movement, vesicular trafficking and pathogen infection. Large families of membrane-binding proteins were recently found to interact with WASP and WAVE family proteins, therefore providing a new layer of membrane-dependent regulation of actin polymerization.

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Figure 1: Domains and basic binding partners of N-WASP and WAVE2.
Figure 2: WASP and WAVE interactors.
Figure 3: Phylogenetic analysis of WASP- and WAVE-binding proteins that have BAR, EFC or RCB/IMD domains.
Figure 4: Functional models of WASP and WAVE proteins in inward or outward deformation of the membrane.
Figure 5: Regulation of inward or outward protrusions of the cell membrane.

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan

    Tadaomi Takenawa & Shiro Suetsugu

  2. PRESTO, JST, 4-1-8, Honcho, Kawaguchi City, 332-0012, Saitama, Japan

    Shiro Suetsugu

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  1. Tadaomi Takenawa
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Correspondence to Tadaomi Takenawa.

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Supplementary information

Supplementary information S1 (table)

Binding partners of WASP/WAVE family proteins and their proposed functions (PDF 322 kb)

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DATABASES

OMIM

CYFIP1

WAS

FURTHER INFORMATION

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Glossary

Thrombocytopenia

The presence of fewer than usual platelets.

Eczema

A state of inflammation of the skin that is characterized by redness, skin oedema, itching and dryness.

ARP2/3 complex

(Actin-related protein-2/3 complex). A complex that consists of seven subunits. ARP2 and ARP3 are thought to function as two of the three actin monomers that are required for the nucleation of actin polymerization.

BAR domain

A dimeric coiled-coil domain found in Bin1, amphiphysin, Rvs167, endophilin and related molecules. The BAR domain is curved with positive charges on its concave surface. The curved surface of the BAR domain is thought to correspond to the curvature of the cell membrane or the membrane tubules.

EFC domain

(Extended Fer-CIP4 homology domain; also known as the FCH-BAR (F-BAR) domain). A dimeric coiled-coil domain that has weak similarity to the BAR domain. This domain is found in the pombe-Cdc15-homology (PCH) family of proteins.

IRSp53

An adaptor protein that contains an N-terminal Rac-binding (RCB) domain, which binds to Rac, actin filaments and the cell membrane. Its C-terminal Src-homology-3 (SH3) domain binds to WAVE2, Ena (also known as VASP) and other proteins, and its CDC42/Rac-interactive binding (CRIB) region is responsible for binding to CDC42.

Filopodium

A spiky structure that protrudes from the cell. Bundled actin filaments fill the inside of a filopodium.

Lamellipodium

A flat cellular structure that protrudes in the direction of cell movement. Branched actin filaments fill the inside of a lamellipodium.

Podosome

A structure that protrudes into the extracellular matrix and that is enriched in actin filaments, matrix-degrading enzymes, focal adhesion molecules and molecules involved in vesicle trafficking.

Invadopodium

A structure that is similar to a podosome, but larger. Sometimes, podosomes in transformed cells are called invadopodia.

Phosphoinositides

A phospholipid species, members of which function as signalling molecules and contain an inositol ring. There are seven poly-phosphoinositides, PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns(4,5)P2 and PtdIns(3,4,5)P3, corresponding to phosphorylation at the hydroxyl moiety in the inositol ring.

Latrunculin

A natural toxin produced by sponges of the Latrunculia genus. It binds to actin monomers and prevents them from polymerizing.

Nephrin

Nephrin is a cell–cell adhesion molecule that belongs to the immunoglobulin superfamily and is localized at the slit diaphragm of kidney glomerulus. Mutations in the gene that encodes nephrin have been associated with the congenital nephrotic syndrome.

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Takenawa, T., Suetsugu, S. The WASP–WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8, 37–48 (2007). https://doi.org/10.1038/nrm2069

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