Structure and control of the actin regulatory WAVE complex

Chen, Zhucheng; Borek, Dominika; Padrick, Shae B.; Gomez, Timothy S.; Metlagel, Zoltan; Ismail, Ahmed Rageh; Umetani, Junko; Billadeau, Daniel D.; Otwinowski, Zbyszek; Rosen, Michael K.

doi:10.1038/nature09623

Cited by 443 publications

(739 citation statements)

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“…Recent structural studies of WRC indicate that its plasma membrane localisation is mediated by Sra1-Rac1 interactions that would release the SCAR/WAVE VCA domain for Arp2/3 activation (Chen et al, 2010). However, WRC-Rac1 interactions are of low affinity suggesting recruitment and activation of WRC requires additional factors (Davidson and Insall, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Purified mammalian WRC is inactive, but can be activated in buffer by high concentrations of Rac1 (Ismail et al, 2009). The low affinity of Rac1 for WRC (Chen et al, 2010) suggested that additional unknown factors are required to facilitate WRC-dependent actin polymerisation (Davidson and Insall, 2011). We showed that active Rac1 was indeed insufficient for recruitment and activation of the WRC at the membrane in mammalian cell extract (Koronakis et al, 2011).…”

Section: Introductionmentioning

confidence: 89%

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The Drosophila Arf1 homologue Arf79F is essential for lamellipodium formation

Humphreys

Liu

Davidson

et al. 2012

Journal of Cell Science

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SummaryThe WAVE regulatory complex (WRC) drives the polymerisation of actin filaments located beneath the plasma membrane to generate lamellipodia that are pivotal to cell architecture and movement. By reconstituting WRC-dependent actin assembly at the membrane, we recently discovered that several classes of Arf family GTPases directly recruit and activate WRC in cell extracts, and that Arf cooperates with Rac1 to trigger actin polymerisation. Here, we demonstrate that the Class 1 Arf1 homologue Arf79F colocalises with the WRC at dynamic lamellipodia. We report that Arf79F is required for lamellipodium formation in Drosophila S2R+ cells, which only express one Arf isoform for each class. Impeding Arf function either by dominant-negative Arf expression or by Arf doublestranded RNA interference (dsRNAi)-mediated knockdown uncovered that Arf-dependent lamellipodium formation was specific to Arf79F, establishing that Class 1 Arfs, but not Class 2 or Class 3 Arfs, are crucial for lamellipodia. Lamellipodium formation in Arf79F-silenced cells was restored by expressing mammalian Arf1, but not by constitutively active Rac1, showing that Arf79F does not act via Rac1. Abolition of lamellipodium formation in Arf79F-silenced cells was not due to Golgi disruption. Blocking Arf79F activation with guanine nucleotide exchange factor inhibitors impaired WRC localisation to the plasma membrane and concomitant generation of lamellipodia. Our data indicate that the Class I Arf GTPase is a central component in WRC-driven lamellipodium formation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

The Drosophila Arf1 homologue Arf79F is essential for lamellipodium formation

Humphreys

Liu

Davidson

et al. 2012

Journal of Cell Science

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“…Rac1 has been shown to activate WAVE proteins through an interaction with the WRC component CYFIP1/ 2 (Chen et al, 2010). In addition, Arf1 has been found to cooperate with Rac1 in activating the WRC (Koronakis et al, 2011).…”

Section: Jmymentioning

confidence: 99%

“…WAVE proteins are intrinsically inactive and exist in a pentameric complex known as the WAVE regulatory complex (WRC), which includes ABI1 or ABI2, NAP1 (also known as NCKAP1) or NCKAP1L, CYFIP1 or CYFIP2 and HSPC300 (Chen et al, 2010;Eden et al, 2002;Ismail et al, 2009;Stradal et al, 2004) (see poster). Rac1 has been shown to activate WAVE proteins through an interaction with the WRC component CYFIP1/ 2 (Chen et al, 2010).…”

Section: Jmymentioning

confidence: 99%

Cellular functions of WASP family proteins at a glance

Alekhina

Burstein

Billadeau

2017

Journal of Cell Science

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165

172

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Proteins of the Wiskott–Aldrich syndrome protein (WASP) family function as nucleation-promoting factors for the ubiquitously expressed Arp2/3 complex, which drives the generation of branched actin filaments. Arp2/3-generated actin regulates diverse cellular processes, including the formation of lamellipodia and filopodia, endocytosis and/or phagocytosis at the plasma membrane, and the generation of cargo-laden vesicles from organelles including the Golgi, endoplasmic reticulum (ER) and the endo-lysosomal network. Recent studies have also identified roles for WASP family members in promoting actin dynamics at the centrosome, influencing nuclear shape and membrane remodeling events leading to the generation of autophagosomes. Interestingly, several WASP family members have also been observed in the nucleus where they directly influence gene expression by serving as molecular platforms for the assembly of epigenetic and transcriptional machinery. In this Cell Science at a Glance article and accompanying poster, we provide an update on the subcellular roles of WHAMM, JMY and WASH (also known as WASHC1), as well as their mechanisms of regulation and emerging functions within the cell.

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“…PKC has lipid binding modules that require independent binding to phosphatidylinositol-4,5-bisphosphate (PIP 2 ), diacylglycerol (DAG), and Ca 2+ for efficient membrane localization. Similarly, the WAVE complex undergoes a sequence of interactions with GTPases, acidic phospholipids, and PIP 3 before activation (Chen et al, 2010;Kim et al, 2000;Lebensohn and Kirschner, 2009;Prehoda et al, 2000). In both cases, coincidence detection has the effect of producing spatial and temporal specificity, as well as a threshold-like response (Carlton and Cullen, 2005;Lemmon, 2008).…”

Section: Introductionmentioning

confidence: 99%

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

Chung

Nocka

Wang

et al. 2018

Preprint

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The transformation of molecular binding events into cellular decisions is the basis of most biological signal transduction. A fundamental challenge faced by these systems is that protein-ligand chemical affinities alone generally result in poor sensitivity to ligand concentration, endangering the system to error. Here, we examine the lipid-binding pleckstrin homology and Tec homology (PH-TH) module of Bruton's tyrosine kinase (Btk) Using fluorescence correlation spectroscopy (FCS) and membrane-binding kinetic measurements, we identify a self-contained phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ) sensing mechanism that achieves switch-like sensitivity to PIP 3 levels, surpassing the intrinsic affinity discrimination of PIP 3 :PH binding. This mechanism employs multiple PIP 3 binding as well as dimerization of Btk on the membrane surface. Mutational studies in live cells confirm that this mechanism is critical for activation of Btk in vivo. These results demonstrate how a single protein module can institute a minimalist coincidence detection mechanism to achieve high-precision discrimination of ligand concentration.All rights reserved. No reuse allowed without permission.

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Structure and control of the actin regulatory WAVE complex

Cited by 443 publications

References 50 publications

The Drosophila Arf1 homologue Arf79F is essential for lamellipodium formation

The Drosophila Arf1 homologue Arf79F is essential for lamellipodium formation

Cellular functions of WASP family proteins at a glance

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

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