Regulation of WASP/WAVE proteins: making a long story short

Abstract

Despite their homology, the regulation of WASP and WAVE, activators of Arp2/3-dependent actin polymerization, has always been thought to be different. Several recent studies have revealed new aspects of their regulation, highlighting its complexity and the crucial role of post-translational modifications. New data also suggest additional functions for WASP family proteins, pushing us to reconsider existing models.

Figure 1.

Model for N-WASP regulation. Under resting conditions, N-WASP is maintained in an inactive state in the cytosol. Autoinhibition is via interaction of the GBD and the C domain of the VCA module. Alternatively, direct interaction with the basic-rich region could inhibit the activity of a prebound Arp2/3 complex. In response to extracellular stimuli, N-WASP autoinhibition is relieved by the binding of GTP-bound Cdc42 and PtdIns(4,5)P₂ (PIP₂) or SH3 containing proteins (SH3). In the open conformation, N-WASP can be imported into the nucleus, where it may be retained by FBP11 and regulate gene expression. Alternatively, active N-WASP can stay in the cytosol. Phosphorylation by tyrosine kinases enhances the ability of N-WASP to activate the Arp2/3 complex in cooperation with F-actin, prevents its nuclear import, and may induce—in certain models—its degradation through the proteasome pathway.

Figure 2.

Model for WAVE regulation. In this model, WAVE constitutively interacts with the Arp2/3 complex. However, in resting conditions Arp2/3 is not activated, either because binding of WAVE to the PIR121-Nap1-Abi-HSPC300 complex prevents the interaction of WAVE-Arp2/3 with an essential coactivator (e.g., F-actin) or because it is mislocalized. The involvement of an inhibitory protein, similar to Sla1 and Bbc1 (indicated by ?, see text for details), has not been ruled out. Extracellular stimuli, through the activation or Rac or the mobilization of Nck, recruit the pentameric complex to the plasma membrane. WAVE activation requires its proper localization plus, in this model, the presence of F-actin and/or the release of the additional protein(s). Alternatively, a complex composed of WAVE, HSPC300, and Arp2/3 is released first, and then activation takes place in the presence of F-actin and the signal is terminated by the degradation of free WAVE proteins.