Rac1 activation comes full circle
2011; Springer Nature; Volume: 30; Issue: 19 Linguagem: Inglês
10.1038/emboj.2011.330
ISSN1460-2075
Autores Tópico(s)Cell Adhesion Molecules Research
ResumoHave you seen?5 October 2011free access Rac1 activation comes full circle Marc Symons Corresponding Author Marc Symons Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY, USA Search for more papers by this author Marc Symons Corresponding Author Marc Symons Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY, USA Search for more papers by this author Author Information Marc Symons 1 1Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, Manhasset, NY, USA *Correspondence to: [email protected] The EMBO Journal (2011)30:3875-3877https://doi.org/10.1038/emboj.2011.330 There is an Article (October 2011) associated with this Have you seen?. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The Rac1 small GTPase is responsive to a large array of extracellular signals and in turn controls a wide variety of cellular functions—including actin dynamics. New findings add an additional layer of intricacy to the already complex process of regulating Rac1 activity, via a positive feedback loop involving the actin-binding protein coronin 1A, the Rac1 exchange factor ArhGEF7, the Rac1 effector Pak1 and the Rac1 inhibitor RhoGDIα. This complex shows remarkable versatility, integrating Rac1 translocation, release from RhoGDI and, possibly, nucleotide exchange. Rac1 orchestrates the assembly of actin-based structures, including lamellipodia and invadopodia, which are involved in directional processes such as cell migration and invasion (Chuang et al, 2004). Precise spatiotemporal control of Rac1 activation is critically important for these events (Bustelo et al, 2007; Berzat and Hall, 2010). Accordingly, localized Rac1 activity is subject to complex control mechanisms that involves tight regulation of GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange factors (Rho GEFs) (Rossman et al, 2005; Garcia-Mata et al, 2011). Binding of Rac1 to RhoGDIs blocks its interaction with GEFs, downstream effectors and GTPase activating proteins, which stimulate intrinsic GTP hydrolysis. In addition, RhoGDIs, by shielding the GTPase prenyl group that serves as a lipid anchor to phospholipid bilayers, prevents access of Rac1 to membrane binding sites. The interaction between Rac1 and RhoGDI is regulated by protein kinases and phospholipids. For example, phosphorylation of RhoGDI by the Rac1 effector Pak1 weakens its interaction with Rac1 (Garcia-Mata et al, 2011), raising the possibility of a positive feedback loop that enhances Rac1 activation. GEFs are also regulated by multiple mechanisms, including phosphorylation and interaction with phosphatidylinositol lipids and an array of protein binding partners (Rossman et al, 2005). Another mode of regulating localized Rac1 activation involves a number of docking proteins, that include ArhGEF7 (also known as Cool1 or βPIX) (ten Klooster et al, 2006). Binding of Rac1 to ArhGEF7 directs Rac1 to the plasma membrane and focal adhesions in the leading edge of migrating cells. The Rac1–ArhGEF7 interaction occurs via a proline stretch in Rac1's C-terminal hypervariable domain and is compatible with GDI binding. To identify new proteins that facilitate translocation of Rac1 to the plasma membrane, Bustelo and colleagues performed a genome-wide functional screen for regulators of Rac1 localization (Castro-Castro et al, 2011). One of the proteins identified was the actin-binding protein coronin 1A. Coronins interact with a number of cytoskeletal proteins and have multiple modes of action, with the overall result of increasing the turnover of actin filaments, thereby promoting cell migration (Chan et al, 2011). Castro-Castro et al found that ectopic expression of coronin 1A is sufficient to translocate Rac1 from the cytosol to the plasma membrane and to increase the level of active Rac1. They also showed that coronin 1A accumulates in lamellipodia, the signature Rac1-regulated actin-based structure at the cell periphery. Thus, coronin 1A is in the right place to control Rac1 activation. Furthermore, siRNA-mediated depletion of coronin 1A blunted Rac1 activation induced by EGF, integrin ligation and T-cell receptor activation, indicating that coronin 1A functions in a wide variety of signalling pathways that promote Rac1 activation. How does coronin 1A mediate Rac1 activation? The authors provide evidence that coronin 1A forms a multi-protein complex that also contains ArhGEF7, Pak1 and RhoGDIα. Phosphorylation of RhoGDIα by Pak1 releases Rac1 from RhoGDIα, allowing nucleotide exchange of the GTPase by Rho GEFs. Like other GEFs of the Dbl family, ArhGEF7 contains a Dbl homology (DH) domain that harbours the catalytic activity of these GEFs. However, it is still controversial whether the DH domain of ArhGEF7 is actually catalytically active. It is also possible that other GEFs associate with the complex. Precisely how the coronin 1A complex is assembled at the molecular level largely remains to be elucidated. Coronin 1A and ArhGEF7 appear to constitute the core of the complex and the interaction of Pak1 and RhoGDIα with coronin 1A is ArhGEF7 dependent. While ArhGEF7 is known to bind to PAK via its SH3 domain—how RhoGDI docks onto the coronin 1A complex remains to be determined. Interestingly, Castro-Castro et al show that proper localization of coronin 1A and formation of the coronin 1A-based multi-protein complex are itself dependent on Rac1 activity as well as on the presence of lipid rafts, cholesterol-rich membrane domains that have been shown to be enriched in active Rac1 (del Pozo et al, 2004). These findings strongly suggest that coronin 1A and its binding partners can establish a positive feedback loop that contributes to sustained Rac1 activation (Figure 1). Figure 1.A coronin 1A-based multi-protein complex mediates a positive feedback loop that contributes to sustained Rac1 activation. Initial activation of Rac1 stimulates actin polymerization (1). Recruitment of a core complex containing coronin 1A and ArhGEF7 to actin filaments (2) ‘activates’ this complex, which allows it to recruit Pak1 (3) and subsequently the RhoGDIα–Rac1 complex (4). Pak1-mediated phosphorylation of RhoGDIα facilitates release of Rac1 (5) and subsequent nucleotide exchange (6). Download figure Download PowerPoint Recently, another multi-protein complex that contains PAK1, RhoGDI and Rac1 has been characterized. This complex appears to centre on diacylglycerol kinase ζ (DGKζ; Abramovici et al, 2009). DGKζ uses the lipid second messenger diacylglycerol as a substrate to produce phosphatidic acid, which in turn activates Pak1. In addition, DGKζ binds to syntrophin, a scaffold protein of the dystrophin glycoprotein complex. The existence of these two complexes raises a number of intriguing questions. Do they mediate the activation of Rac1 by different stimuli, or do they selectively relay signalling to different elements that act downstream of Rac1, or a combination of both? Another possibility is that these two complexes largely operate in different cell types. It is interesting to note that coronins interact with and inhibit the function of the actin nucleating Arp2/3 protein complex (Chan et al, 2011), whereas Rac1-mediated signalling via WAVE proteins is critical for the activation of Arp2/3 in lamellipodia. One interpretation of this paradox could be that the dual functions of coronin 1A in the regulation of actin turnover and Rac1 activation reflect the existence of distinct pools of coronin 1A that mediate different functions, depending on the nature of its binding partners. Spatial restriction of functionally interacting signalling components is an efficient way of ensuring the specificity of information flow in signalling networks (Good et al, 2011). One way to accomplish this is by compartmentalization on organelles such as endosomes or on plasma membrane microdomains. Another way is to assemble a multi-protein complex, as is illustrated in this paper by Bustello and colleagues. Indeed, the coronin 1A-based complex functions as an organizing centre that facilitates multiple steps of the Rac1 activation process, including translocation of Rac1 from the cytosol to the plasma membrane, release from RhoGDI and possibly, nucleotide exchange. The authors also show that the coronin 1A complex is selective for Rac1 and that it does not act on either Cdc42 or RhoA, although it does translocate RhoG, a GTPase that is closely related to Rac1. Thus, it will be of great interest to find out if similar complexes exist to facilitate the activation of other Rho family members. Conflict of Interest The author declares that he has no conflict of interest. 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