WASPs and WAVEs

Discovery

In humans, the WASP/WAVE family is divided into two main subfamilies, ie, the WASP subfamily (referred to as WASPs) and WAVE subfamily (referred to as WAVEs). The first member of the WASPs to be identified was WASP itself, mutations of which were found to be the cause of WAS.11


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WAS is an X-linked recessive disorder initially described in patients suffering with thrombocytopenia, eczema, and immunode­ficiency,12 now commonly labeled the clinical triad of WAS symptoms.

Patients exhibit varied severity of symptoms, with some suffering the full classic triad of clinical manifestations and often not surviving until adulthood, whereas others dem­onstrate a milder phenotype and have an improved survival rate.13

Different mutations of the WASP gene have been linked to the varied phenotypes of WAS, with evidence that mutations disrupting the activity of the important functional domains lead to more severe phenotypes.14,15

Family members

A molecule identified in the brain, but widely expressed in different tissues, which shares several functional motifs with WASP, was named neural WASP (nWASP) and is the second member of the WASP subfamily.16

WAVE1 (also referred to as Scar1, suppressor of cAR1) was first identified in 1998 as a regulator of the actin cytoskeleton through interactions with Arp2/3 downstream of Rac.17,18

Following identification of WAVE1, two further WAVE homologs, which were also found to associate with the Arp2/3 complex, were characterized and named WAVE2 and WAVE3.19

Novel members of the WASP/WAVE family have recently been identified based on the resemblance between characteristic domains in their pro­tein structure. These are WASP and SCAR homolog, WASP homolog associated with actin, membranes, and microtu­bules, and junction mediating and regulatory protein.20–22

Structure

nWASP shares several multifunctional domains with WASP, including the WASP homology domain, GTPase-binding domain/Cdc42, and Rac interactive binding (GBD/CRIB) domain, a proline-rich region and VCA domain consisting of a verprolin-homology (V) region, a cofilin-like (C) region, and an acidic (A) region (Figure 1B, adapted from Takenawa and Suetsugu9).

The WAVE family consists of WAVE1, WAVE2, and WAVE3, all of which have a WAVE homol­ogy domain but lack the GBD/CRIB domain and, like the WASPs, have a basic region, a proline-rich region, and a VCA domain.23

Endogenous WAVEs assemble into a heterologous, multimolecular complex referred to as the WAVE complex. The multiprotein complex associated with WAVE1 was first described as comprising several components, namely, p53-inducible messenger RNA (also called Rac2 associated protein/Sra1), NCK-associated protein, hematopoietic stem/progenitor cell protein 300, and Abl interactor 2.24

Complexes consisting of the same proteins, or their paralogs, as described for the WAVE1 complex were later identified for WAVE2 and WAVE3 as well.25–27

Activation of the WASP/WAVE family

The WASP/WAVE family regulates actin dynamics through interactions with many other factors, in particular, the Arp2/3 complex. Arp2/3 becomes activated when bound to the CA region on the C-terminal of WASP/WAVE proteins and initiates actin polymerization when bound in conjunction with an actin monomer binding to the V region.18,23,28,29 This interaction is the most important in terms of WASP func­tion, but many other binding partners regulate WASP and WAVE activation.

Under resting conditions, nWASP and WASP exist in an autoinhibited, folded conformation where an interaction between the GBD domain in the N-terminal region and the C-terminus masks the VCA region. This interaction inhibits access of the Arp2/3 complex to the CA region and so WASP and nWASP remain inactive.30,31

The competitive binding of ligands such as Rho GTPase, Cdc42, and phosphati­dylinositol 4,5-bisphosphate (PIP2) with WASPs can disrupt the interactions between the C-termini and N-termini that mask the VCA region. Cdc42 binds to GBD and PIP2 can interact with the basic region.

Either of these interactions can destabilize the autoinhibited conformation of WASPs and enhance the binding of the other ligand, leading to exposure of the VCA region and activation of WASP family proteins.32,33

The mechanism of activation of WAVEs has been the subject of debate for many years. It is now clear that the native form of WAVEs, in a multiprotein complex, is inac­tive with inhibited actin polymerization ability.34

This has been confirmed by studies examining the reconstitution of the WAVE complex and purified native WAVE complexes. These independent reports also suggest that WAVEs are inhibited in a similar fashion to WASPs, ie, through masking of the VCA region by interactions in the WAVE complex.35,36

Since WAVEs do not possess a GBD like WASPs, they do not directly interact with Rho-GTPases; however, they do act as downstream effectors of the Rho-GTPase Rac, as well as other signals.17 A conformational change brought about by Rac binding to the Sra component of the WAVE complex seems to release the VCA region.35

Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) has also been implicated in the mechanism of activation of WAVEs. It has been shown that PIP3 recruits the WAVE complex to the plasma membrane through binding to the basic domain of WAVE2 and acts in synergy with IRSp53 (also called brain-specific angio­genesis inhibitor 1-associated protein 2) to activate WAVE2 through Rac activity.37,38

For comprehensive information on the mechanisms of activation of the WASP/WAVE family, see reviews that have covered this in more detail.9,39