Model depicting mechanisms for activation of WASp. WASp is a multimodular protein, including an N-terminal EvH1 domain, a short basic region (BR) adjacent to a GTPase binding domain (GBD), a polyproline domain, and a tripartite C-terminal VCA domain (see main text for details). The majority of cytosolic WASp is complexed with WIP, which binds to the EvH1 domain. In the inactive state, WASp adopts an autoinhibited configuration in which the C region of the VCA module interacts with the GBD and adjacent sequences. In this configuration, either Arp2/3 complex cannot be bound or is inactive. WIP appears to play an important role in maintaining this configuration in the absence of activating signals. Activation following cell stimulation is initiated by several factors including GTP-bound CdC42, PIP₂, and many SH3 domain containing proteins that in some cases are responsible for phosphorylation of Y291. These individual factors may operate cooperatively, but may also be redundant for activation depending on the context. Destabilization of the autoinhibited conformation of WASp permits the initiation of actin polymerization for monomeric g-actin by the Arp2/3 complex. Toca-1 is essential for Cdc42 and PIP₂-induced actin polymerization, and binds to both Cdc42 and a WIP-WASp complex through the SH3 domain of Toca-1. It is not clear whether Toca-1 can interact directly with WIP, or whether the WIP-WASp complex dissociates after binding.