Actin reorganization is crucial in many biological processes such as cell locomotion and maintenance of cell shape. The Cdc42/Rac1 small GTPase signaling pathway has emerged as a major pathway mediating de novo assembly of actin. Upon activation by external signals, Cdc42/Rac1 switch into their active forms and activate WASP proteins, which in turn bind to the Arp2/3 complex and activate its actin-nucleation activity.In order to avoid constitutive activation of the Arp2/3 complex, its interaction with WASP proteins is tightly regulated. All WASP family proteins (WASP, N-WASP, WAVE1, WAVE2 and WAVE3) contain a C-terminal WA domain, which binds to and activates the Arp2/3 complex, and various N-terminal regulatory domains [1xSpatial and temporal regulation of actin polymerization for cytoskeleton formation through Arp2/3 complex and WASP/WAVE proteins. Suetsugu, S. et al. Cell Motil. Cytoskeleton. 2002; 51: 113–122Crossref | PubMed | Scopus (47)See all References][1]. Isolated WASP and N-WASP exist in an autoinhibited conformation, owing to the interaction between the WA domain and an N-terminal basic motif. Binding of Cdc42 to WASP/N-WASP dissociates this intramolecular interaction and unmasks the WA domain, allowing its interaction with the Arp2/3 complex. Unlike WASP/N-WASP, isolated WAVE proteins exist in the activated form. Although WAVE proteins act downstream of Rac, they do not interact directly with Rac. Until recently, the mechanism of regulation of WAVE proteins was unknown. IRSp53, an insulin receptor substrate, was identified as a link between WAVE2 and Rac [2xIRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Miki, H. et al. Nature. 2000; 408: 732–735Crossref | PubMed | Scopus (390)See all References][2]. However, it is unclear how IRSp53 couples Rac activation to WAVE2. Now, Kirschner and colleagues have found a novel complex that acts as a WAVE1 trans-inhibitory complex [3xThe mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Eden, S. et al. Nature. 2002; 418: 790–793Crossref | PubMed | Scopus (492)See all References][3].In a search for WAVE1-binding proteins in bovine brain extracts, the authors identified a 500-kDa complex comprising WAVE1, PIR121 (a Rac1-binding protein), Nap125 (an Nck-binding protein), Abi2 (‘Abl-interactor 2’ – homologous to hNap1-binding protein) and a novel 9-kDa protein, HSPC300. In this complex, WAVE1 is unable to activate Arp2/3 complexes. Both RacGTPγS and Nck can relieve this inhibition. RacGTPγS and Nck dissociate the complex into two subcomplexes, the first comprising PIR121, Nap125 and probably Rac or Nck and a second subcomplex comprising HSPC300 and WAVE1. The HSPC300–WAVE1 subcomplex is able to activate the Arp2/3 complex. Very little is known about PIR121 and Nap125. PIR121 has been described as a potential mediator of p53-dependent apoptosis and as interacting with fragile-X mental retardation protein (FMRP), an RNA-binding protein associated with a messenger ribonucleoprotein complex. This suggests that, after dissociation from the WAVE1 complex, the PIR121–Nap125 subcomplex might participate in a currently uncharacterized translational/transcriptional processes. Thus, the complex reported in this work gives us a first glimpse into how WAVE proteins are regulated and provides a nice tool for understanding how the cellular machinery coordinates different cellular processes.
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