The Rho Family GTPase Rif Induces Filopodia through mDia2

Mammalian Cell Biology Laboratory, Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
Current Biology (Impact Factor: 9.92). 02/2005; 15(2):129-33. DOI: 10.1016/j.cub.2005.01.011
Source: PubMed

ABSTRACT Eukaryotic cells produce a variety of specialized actin-rich surface protrusions. These include filopodia-thin, highly dynamic projections that help cells to sense their external environment. Filopodia consist of parallel filaments of actin, bundled by actin crosslinking proteins. The filaments are oriented with their rapidly growing "barbed" ends at the protruding tip and their slowly growing "pointed" ends at the base. Extension occurs by polymerization at the tip and is controlled by regulation of filament capping. The Rho GTPase Cdc42 is a key mediator of filopodia formation, which it regulates through binding CRIB domain-containing effectors. Cdc42 binds and activates the WASP proteins, which in turn activate the actin-nucleating complex Arp2/3. It also binds and activates IRSp53, which recruits the Ena/WASP family protein Mena to the filopodial tip and protects elongating actin filaments from capping. Previously, we identified another Rho family GTPase, Rif, as a potent stimulator of filopodial protrusion through a mechanism that does not require Cdc42. Here we characterize the differences between filopodia induced by these two small GTPases and show that the Rif effector in this pathway is the Diaphanous-related formin mDia2. Thus, Rif and Cdc42 represent two distinct routes to the induction of filopodia-producing structures with both shared and unique properties.

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Available from: Harry Mellor, Aug 23, 2015
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    • "Interestingly, inside filopodia, GFP-Simiate localizes mainly to the head (Figure 4A) as does endogenous Simiate in filopodia from neuronal growth cones (cp. Figure 5A), supporting the idea that Simiate is indeed involved in the exploration behavior of filopodia by regulating Actin polymerization in the filopodia tip (cp. Berg and Cheney, 2002; Svitkina et al., 2003; Lebrand et al., 2004; Yamagishi et al., 2004; Millard et al., 2005; Pellegrin and Mellor, 2005; Schirenbeck et al., 2006; Dent et al., 2007; Goh et al., 2011). "
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    ABSTRACT: The Actin cytoskeleton constitutes the functional base for a multitude of cellular processes extending from motility and migration to cell mechanics and morphogenesis. The latter is particularly important to neuronal cells since the accurate functioning of the brain crucially depends on the correct arborization of neurons, a process that requires the formation of several dozens to hundreds of dendritic branches. Recently, a model was proposed where different transcription factors are detailed to distinct facets and phases of dendritogenesis and exert their function by acting on the Actin cytoskeleton, however, the proteins involved as well as the underlying molecular mechanisms are largely unknown. Here, we demonstrate that Simiate, a protein previously indicated to activate transcription, directly associates with both, G- and F-Actin and in doing so, affects Actin polymerization and Actin turnover in living cells. Imaging studies illustrate that Simiate particularly influences filopodia dynamics and specifically increases the branching of proximal, but not distal dendrites of developing neurons. The data suggests that Simiate functions as a direct molecular link between transcription regulation on one side, and dendritogenesis on the other, wherein Simiate serves to coordinate the development of proximal and distal dendrites by acting on the Actin cytoskeleton of filopodia and on transcription regulation, hence supporting the novel model.
    Frontiers in Cellular Neuroscience 04/2014; 8:99. DOI:10.3389/fncel.2014.00099 · 4.18 Impact Factor
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    • "However, activation is noticeably incomplete (Li and Higgs, 2003; Maiti et al., 2012), suggesting that other factors are required to fully activate formins. A variety of Rho-GTPases recruit DRFs to different locations in the cell for localized actin assembly (Evangelista et al., 1997; Watanabe et al., 1997; Ishizaki et al., 2001; Nakano et al., 2002; Tolliday et al., 2002; Pellegrin and Mellor, 2005; Seth et al., 2006; Martin et al., 2007; Block et al., 2012) (see Poster), yet additional factors can also regulate formins. For example, the S. cerevisiae formin Bnr1 and S. pombe formin Cdc12 each harbor at least two separate localization sequences that independently target the formin in vivo (Gao et al., 2010), suggesting that a combination of cues and binding partners control formin recruitment. "
    Journal of Cell Science 03/2013; 126(Pt 1):1-7. DOI:10.1242/jcs.107250 · 5.33 Impact Factor
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    • "Factors such as VASP family members or ill-defined components of the filopodia tip complex may then promote the transient association of actin filaments, which can be further stabilized by other bundlers, such as fascin, thus permitting the formation of actin bundles and filopodia (Mogilner & Rubinstein, 2005). According to the de novo nucleation model, formins (Pellegrin & Mellor, 2005; Schirenbeck et al., 2005; Yang et al., 2007; Block et al., 2008) or VASP tetramers, particularly when clustered along the plasma membrane (Breitsprecher et al., 2008, 2011; Hansen & Mullins, 2010), may be responsible for promoting filopodial initiation. Also in this case, however, filaments must be protected from cappers, which have been shown, in the case of the capping protein (CP), to compete, either directly or indirectly, with VASP as well as with formins for barbed-end binding (Breitsprecher et al., 2008). "
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    ABSTRACT: Actin-capping and anti-capping proteins are crucial regulators of actin dynamics. Recent studies have indicated that these proteins may be heavily involved in all stages of synaptogenesis, from the emergence of filopodia, through neuritogenesis and synaptic contact stabilization, to the structural changes occurring at the synapse during potentiation phenomena. In this review, we focus on recent evidence pointing to an active role of actin-capping and anti-capping proteins in orchestrating the processes controlling neuronal connectivity and plasticity.
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