Wash functions downstream of Rho and links linear and branched actin nucleation factors

Liu, Raymond; Abreu-Blanco, María Teresa; Barry, Kevin C.; Linardopoulou, Elena V.; Osborn, Gregory E.; Parkhurst, Susan M.

doi:10.1242/dev.035246

Cited by 107 publications

(170 citation statements)

References 49 publications

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“…Yet, the shared assembly and regulatory function of the WRC and SHRC suggests the possibility that WASH may be similarly activated. Interestingly, a recent report showed that WASH functions downstream of RhoA during Drosophila oocyte development (20). However, in contrast to this report, we have been unable to identify an interaction of RhoA with the assembled SHRC or activation (Fig.…”

Section: Resultscontrasting

confidence: 95%

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WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

Jia

Gomez

Metlagel

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

202

325

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We recently showed that the Wiskott-Aldrich syndrome protein (WASP) family member, WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibited, suggesting that it functions in cells to regulate actin dynamics through WASH. FAM21 interacts directly with CAPZ and inhibits its actin-capping activity. Four of the five core components show distant (approximately 15% amino acid sequence identify) but significant structural homology to components of a complex that negatively regulates the WASP family member, WAVE. Moreover, biochemical and electron microscopic analyses show that the WASH and WAVE complexes are structurally similar. Thus, these two distantly related WASP family members are controlled by analogous structurally related mechanisms. Strumpellin is mutated in the human disease hereditary spastic paraplegia, and its link to WASH suggests that misregulation of actin dynamics on endosomes may play a role in this disorder.actin dynamics and capping | endosome | WAVE regulatory complex | WASH regulatory complex | hereditary spastic paraplegia

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Section: Resultscontrasting

confidence: 95%

“…2B). Full-length WASH was highly active, suggesting that WASH is not autoinhibited like WASP and N-WASP (20). In contrast to the WASH VCA, highly purified recombinant SHRC had no measurable activity toward Arp2/3 complex.…”

mentioning

confidence: 93%

WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

Jia

Gomez

Metlagel

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

202

325

View full text Add to dashboard Cite

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“…Interestingly, the SHRC appears structurally related to the WAVE regulatory complex (WRC), both in terms of complex assembly and the similarity in shape and size as determined by electron microscopy of the two complexes (Jia et al, 2010). While studies in Drosophila melanogaster have revealed a role for Rho1 in activating WASH (Liu et al, 2009), mammalian RhoA did not activate the SHRC in vitro (Jia et al, 2010). WASH activity is regulated by K63-linked polyubiquitylation, which serves to change the conformation of WASH, resulting in exposure of its C-terminal WCA domain (Hao et al, 2013).…”

Section: Jmymentioning

confidence: 99%

“…This is mediated by a TRIM27-containing ubiquitin ligase complex that also contains MAGEL2 and UBE2O, and is regulated by the deubiquitinase USP7 (Hao et al, 2015). Finally, although deletion of WASH in Drosophila was initially found to impair oogenesis and larval development (Linardopoulou et al, 2007;Liu et al, 2009), a recent study using a different WASH mutant showed that homozygous wash mutant flies are viable and fertile (Nagel et al, 2017). This discrepancy was likely caused by a secondsite lethal mutation in the Drosophila strain used in the former studies.…”

Section: Jmymentioning

confidence: 99%

Cellular functions of WASP family proteins at a glance

Alekhina

Burstein

Billadeau

2017

Journal of Cell Science

158

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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“…Three major classes of nucleating proteins have been identified until today: the Arp2/3 complex together with newly identified nucleation-promoting factors such as WASH, WHAMM and JMY (3)(4)(5)(6)(7), formins (8,9), and a third class which comprises the proteins commonly named tandem-monomer-binding nucleators (10). This last group of nucleators contains 17-27 amino acid long actin-binding motifs called the WH2 repeats-the name derived from the Wiskott-Aldrich syndrome protein homology domain 2 (11,12).…”

mentioning

confidence: 99%

Molecular architecture of the Spire–actin nucleus and its implication for actin filament assembly

Sitar

Gallinger

Ducka

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The Spire protein is a multifunctional regulator of actin assembly. We studied the structures and properties of Spire-actin complexes by X-ray scattering, X-ray crystallography, total internal reflection fluorescence microscopy, and actin polymerization assays. We show that Spire-actin complexes in solution assume a unique, longitudinal-like shape, in which Wiskott-Aldrich syndrome protein homology 2 domains (WH2), in an extended configuration, line up actins along the long axis of the core of the Spire-actin particle. In the complex, the kinase noncatalytic C-lobe domain is positioned at the side of the first N-terminal Spire-actin module. In addition, we find that preformed, isolated Spire-actin complexes are very efficient nucleators of polymerization and afterward dissociate from the growing filament. However, under certain conditions, all Spire constructs-even a single WH2 repeat-sequester actin and disrupt existing filaments. This molecular and structural mechanism of actin polymerization by Spire should apply to other actin-binding proteins that contain WH2 domains in tandem.cytoskeleton | nucleation T he first step in the assembly of actin filaments is nucleation (1, 2). Three major classes of nucleating proteins have been identified until today: the Arp2/3 complex together with newly identified nucleation-promoting factors such as WASH, WHAMM and JMY (3-7), formins (8, 9), and a third class which comprises the proteins commonly named tandem-monomer-binding nucleators (10). This last group of nucleators contains 17-27 amino acid long actin-binding motifs called the WH2 repeats-the name derived from the Wiskott-Aldrich syndrome protein homology domain 2 (11, 12). The group consists of Spire (13), , Leiomodin from muscle cells (15), JMY (6), and the recently discovered adenomatous polyposis coli (APC) protein (16). These proteins share the common ability, mediated by WH2 domains, to gather actin monomers into a nucleation complex, but the arrangement of nuclei might vary significantly among these nucleators. Spire contains four consecutive WH2 domains and is the most important representative member of the group. The molecular mechanism of actin nucleation is well described for the Arp2/3 complex (17) and formins (18), whereas several different mechanisms have been proposed for Spire (19)(20)(21)(22), Leiomodin (15), JMY (6), and the APC protein (16). The N-terminal domain of Spire (SpireNT, residues 1-520 in Drosophila melanogaster Spire; see Fig. S1) has the potential to form a string of four actin monomers through the interaction with four WH2 repeats (13,19,20). WH2 motifs are known to be intrinsically disordered, adopting an α-helical structure only upon binding to actin (23). Alignments of WH2 domains indicate that the most conserved regions are the LKK motif and an α-helix at the N terminus, which is shown to be the principal structural actin-binding element that binds to actin in its hydrophobic pocket between actin's subdomains 1 and 3 (20,24,25). The rest of the WH2, including the LKK motif, exten...

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Wash functions downstream of Rho and links linear and branched actin nucleation factors

Cited by 107 publications

References 49 publications

WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

WASH and WAVE actin regulators of the Wiskott–Aldrich syndrome protein (WASP) family are controlled by analogous structurally related complexes

Cellular functions of WASP family proteins at a glance

Molecular architecture of the Spire–actin nucleus and its implication for actin filament assembly

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