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Science at a Glance 2575

WASP and SCAR/WAVE complex (Goley and Welch, 2006), a major Wiskott-Aldrich syndrome, in which initiator of polymerisation that mutations in the encoding WASP : the drivers of promotes the formation of branched actin- cause immune and blood deficiencies, actin assembly filament networks. When the Arp2/3 whereas the dual name of SCAR/WAVE complex was first purified completely, it emerged because the same was 1 Alice Y. Pollitt and Robert H. became clear that the complex was not discovered independently by two groups – 2, Insall * sufficient to initiate new actin filaments on ‘SCAR’ through Dictyostelium discoideum 1Centre for Cardiovascular Sciences, Institute of its own (Machesky et al., 1999). Members genetics (Bear et al., 1998) and ‘WAVE’ by Biomedical Research, College of Medical and of the Wiskott-Aldrich syndrome protein with WASP (Miki et al., 1998). Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK (WASP) family were subsequently SCAR was the first name to be used, for 2Beatson Institute for Cancer Research, Switchback identified as the major regulators of the both the Dictyostelium protein and its Road, Bearsden, Glasgow G61 1BD, UK Arp2/3 complex (Millard et al., 2004); mammalian homologues, but in *Author for correspondence (e-mail: [email protected]) these proteins activate the Arp2/3 complex mammalian cells WAVE is now more to nucleate new actin filaments. The commonly used. Journal of Cell Science 122, 2575-2578 importance of WASP proteins was Published by The Company of Biologists 2009 immediately recognised when it became Both WASPs and SCAR/WAVEs are doi:10.1242/jcs.023879 clear that they were involved in linking present throughout evolutionary history. signalling events to the regulation of the , Dictyostelium The actin plays an essential actin cytoskeleton. and Caenorhabditis elegans possess one of role in numerous aspects of cell , each. possess WASP but no such as cell morphology and . The WASP family consists of two principal SCAR/WAVE, whereas the opposite is true Actin’s role in these processes is tightly classes of protein – WASPs and in plants (Uhrig et al., 2007). Mammals regulated, in particular through the Arp2/3 SCAR/WAVEs. WASPs are named after typically have two WASPS – the Journal of Cell Science

(See poster insert) 2576 Journal of Cell Science 122 (15)

haematopoietic-specific WASP and the which might bind to phosphatidylinositol Phosphorylation is emerging as an ubiquitous N-WASP – and three (4,5)-bisphosphate [PtdIns(4,5)P2] and important mode of regulating the WASP SCAR/WAVE proteins. Other members of other anionic phospholipids and localise family of proteins. Tyrosine phosphoryl- the WASP family are beginning to emerge the proteins to the plasma membrane. ation of WASP leads to an increase in its – WASH (Linardopoulou et al., 2007) Thus, the N-terminal domains define the ability to activate the Arp2/3 complex (which appears to be as universally way in which both WASP and without apparent need for Cdc42 or expressed as WASP and SCAR/WAVE, SCAR/WAVE proteins are regulated, PtdIns(4,5)P2, and serine/threonine phos- although its physiological role has not yet and also to a large extent their subcellular phorylation can stimulate actin polymeris - been studied), and WHAMM (Campellone localisation. ation in vitro; however, the physiological et al., 2008) and JMY (Zuchero et al., significance of phosphorylation in vivo has 2009) (which are recently discovered Regulation of WASP and yet to be demonstrated (Cory et al., 2003). proteins that are specific to metazoa and SCAR/WAVE activity In mammals, tyrosine phosphorylation of have roles in vesicle traffic). In this poster WASP and N-WASP are predominantly WAVE2 by the Abl kinase might be article, we describe the range of found in an autoinhibited conformation in involved in its localisation to the leading physiological functions that have been which the C-terminus of the protein is edge, whereas tyrosine phosphorylation of established for WASP and SCAR/WAVE occluded through its interaction with the WAVE1 by Src increases its affinity for the proteins. WASH, WHAMM and JMY are N-terminus. This autoinhibition is released Arp2/3 complex in vitro (Ardern et al., not discussed further as too little is by the competitive binding of the small 2006). WAVE1 is also basally serine/ currently known about their roles. GTPase Cdc42 and the phospholipid threonine phosphorylated (Kim et al., PtdIns(4,5)P2 (Kim et al., 2000), although 2006), which inhibits its ability to activate Domain structure and interacting it is not clear whether the lipid acts as a the Arp2/3 complex in vitro and in vivo. proteins signalling molecule or merely as an anionic cAMP signalling reduces WAVE1 Members of the WASP family of proteins marker of the plasma membrane (Insall and phosphorylation, which apparently are characterised by a conserved domain Weiner, 2001). Other proteins are thought increases the ability of WAVE1 to activate arrangement (see poster) (Innocenti et al., to bind to WASPs and regulate their the Arp2/3 complex (Kim et al., 2006). 2004). The C-terminus is responsible for activity – WIP is a frequently observed binding to and activating the Arp2/3 binding partner (Ramesh et al., 1997) and The Arp2/3 complex and actin complex. It comprises one or two WASP TOCA1, which (like WASP) binds to assembly homology 2 (WH2) domains, which bind Cdc42, might add selectivity and Actin monomers are present in the to monomeric actin, followed by a short cooperation to the Cdc42-dependent at extremely high levels – actin central (C) region and an acidic (A) activation of WASPs (Ho et al., 2004). The is the most abundant protein in most domain, which interacts with the Arp2/3 role of SH3-domain adaptors such as Nck eukaryotic cells, and more than half of it is complex. Polyproline repeats within the and Grb2 in WASP activation remains a typically monomeric in living cells. Actin proline-rich region provide possible sites mystery; early papers reported that they does not spontaneously polymerise

Journal of Cell Science for the binding of numerous Src-homology bound to the proline-rich domains of both because of a high kinetic barrier. Once 3 (SH3)-domain-containing proteins (see WASP and SCAR, but these have been filaments are initiated, they extend rapidly poster) (Takenawa and Suetsugu, 2007). It relatively unsupported by recent data until they are actively stopped, but a remains to be determined which of these (Buday, 1999). catalyst is required to start a new filament. interactors are physiologically important There are two principal classes of such and how they regulate WASP-family Unlike WASPs, SCAR/WAVE proteins are catalysts, which are usually called proteins in vivo (see below for a discussion not autoinhibited and they form part of a ‘nucleators’ because they nucleate new of WASP and SCAR/WAVE regulation). larger regulatory complex that contains filaments – and the Arp2/3 four other proteins – PIR121, Nap1, Abi complex. Formins generate single actin The organisation of the N-terminal region, and HSPC300 (Eden et al., 2002). The filaments that are typically oriented which contains domains that are thought to small GTPase Rac interacts with the orthogonally to the membrane. However, provide a connection with regulatory complex via the PIR121 subunit, and other the Arp2/3 complex – when it has been proteins, differs among WASP-family as-yet-unknown proteins are likely to activated by a WASP-family protein – members. WASP and N-WASP contain a interact with the other complex members nucleates new actin at a 70° angle from the WASP homology 1 (WH1) domain, also (Ibarra et al., 2006). There has been side of pre-existing filaments, generating a known as an Ena/VASP homology 1 controversy about the dynamics and basal crosslinked, anisotropic meshwork of actin (EVH1) domain, and a CRIB domain, activity of the complex. Eden et al. found (see poster). which binds to the small GTPase Cdc42. that the intact complex was inactive, but The WH1 domain interacts with the that it released an active subcomplex Exactly how members of the WASP family WASP-interacting protein (WIP) family of containing SCAR/WAVE and HSPC300 of proteins interact with the Arp2/3 proteins, and this interaction is thought to when stimulated (Eden et al., 2002). complex to result in its activation remains suppress the activity of WASP or N-WASP. Recent work has not reproduced the to be fully elucidated. The actin-related By contrast, the SCAR/WAVE proteins splitting of the complex, but does indicate subunits of the Arp2/3 complex, Arp2 and contain a SCAR homology domain (SHD), that the pure complex has no activity until Arp3, are proposed to form a ‘pseudo-actin and do not possess any type of GTPase- it is stimulated by upstream signals that dimer’ that nucleates actin polymerisation binding domain. Both WASPs and include Rac and probably additional inputs but, in the open (inactive) conformation, SCARs/WAVEs contain a basic region, (Ismail et al., 2009). Arp2 and Arp3 are too far apart to do this, Journal of Cell Science 122 (15) 2577

suggesting that a conformational change filaments are reorganised by parallel actin- domains of N-WASP to promote a is required. Studies using electron binding proteins (Biyasheva et al., 2004). conformational change that relieves microscopy suggest that the Arp2/3 The relative contributions of the WASP autoinhibition (Egile et al., 1999). complex is in equilibrium between an family to this and other pathways, in open (inactive) and a closed (active) particular those that involve formins, The recruitment of proteins that activate conformation, and that binding of WASP- remain controversial. N-WASP is also exploited by family members locks it into its active state enteropathogenic and enterohaemorrhagic (Rodal et al., 2005). In addition, the WH2 are structures formed by Escherichia coli (EPEC and EHEC, domain seems to recruit a new actin haematopoietic cells and osteoclasts, and respectively) to induce the formation of monomer to the activated Arp2/3 complex, invadopodia are related structures that actin-based pedestals in the host-cell completing the nucleation of a new branch protrude into the matrix from certain types plasma membrane (Caron et al., 2006). (Boczkowska et al., 2008). of invasive cancer cells. The formation of EPEC inject a protein called Tir through these structures is mediated via actin the host-. Tir is Biological functions of WASP- reorganisation and the activation of matrix phosphorylated by host-cell kinases and family proteins metalloproteinases, which degrade the recruits the adapter protein Nck, which The activity of the WASP family of (Buccione et al., activates N-WASP, leading to actin proteins has been implicated in numerous 2004). Activation of the Arp2/3 complex polymerisation and the formation of a biological processes that involve the by N-WASP has been shown to be essential pedestal, which seems to allow EPEC to reorganisation of the actin cytoskeleton for the formation of podosomes and might maintain unusually strong adhesion and (see poster). Their activation can lead to also be essential for invadopodia (Mizutani thus to remain in the host intestine. EHEC the formation of numerous actin-based et al., 2002). use a different mechanism, in which they structures, such as lamellipodia, , inject two proteins, Tir and EspFU (also podosomes and plant trichomes. In Vesicle trafficking and pathogen known as TccP). EspFU binds to and addition to these structural roles, WASP- infection activates the host WASP through a family proteins have central roles in Along with the Arp2/3 complex, WASP repeated amino acid sequence that mimics membrane trafficking, and are manipulated and N-WASP are recruited to sites of the central region of the WASP C-terminal during infection by intracellular pathogens. phagocytosis. There is also evidence that tail and releases autoinhibition (Cheng Other emerging roles include cell-substrate these proteins are involved in - et al., 2008; Sallee et al., 2008). adhesion (Ibarra et al., 2006) and mediated (Qualmann and (Pollitt and Insall, 2008); Kelly, 2000). Several proteins have been Conclusion others will no doubt continue to emerge. shown to interact with both (a key Our understanding of WASP and endocytic mediator) and N-WASP, and SCAR/WAVE proteins is growing fast, but Actin-based structures these might bridge the two proteins during there remains a great deal left to discover. Lamellipodia are sheet-like structures at endocytosis. N-WASP is recruited Newly discovered WASP-family members

Journal of Cell Science the leading edge of the cell, in which actin specifically to the dynamin neck of such as WASH and WHAMM have filaments are arranged into a crosslinked endocytic pits, where it might lead to actin broadened the range of physiological roles network (Pollard and Borisy, 2003). polymerisation; this could provide a of the family, interacting proteins and Electron microscopy reveals that these mechanical force to pinch off . filaments are branched at 70°, which is N-WASP is also implicated in the pathways are only beginning to be characteristic of Arp2/3-complex activity. formation of the actin-comet tails that are discovered, and the mechanisms by which Multiple studies in a range of cell types sometimes found behind vesicles and that physiological events control activation of have shown that SCAR/WAVE proteins are appear to propel them though the the Arp2/3 complex through the WASP required for formation and cytoplasm (Innocenti et al., 2004). family are only partially understood. What typically act downstream of the small is clear is that most functions of the actin GTPase Rac (Kunda et al., 2003; Yan et al., The same mechanisms that result in vesicle cytoskeleton, and probably several other 2003). By contrast, the role of the WASP movement are also thought to be exploited aspects of , depend family in the formation of filopodia – long, by bacterial pathogens to allow them to crucially on WASP and its relatives. This finger-like cell-membrane protrusions that move through the cytoplasm of the infected is an exciting field. contain bundles of straight actin filaments cell using the cell’s own actin. Pathogens We are very grateful to the MRC for a Senior – is much less clear. Earlier work suggested such as Shigella and mycobacteria achieve Fellowship to R.H.I. and project grant support for that N-WASP localises to these structures this by expressing proteins that recruit and A.Y.P., to Laura Machesky for comments, and to the anonymous referees for constructive comments. and that activation of N-WASP by the activate WASP-family proteins in the host Deposited in PMC for release after 6 months. small GTPase Cdc42 leads to their cell. This induces actin polymerisation at formation. However, filopodia can still be the cell surface of the bacterium through References formed in WASP-deficient cells (Snapper activation of the Arp2/3 complex. Actin- Ardern, H., Sandilands, E., Machesky, L. M., Timpson, et al., 2001) and the parallel orientation of based motility of Shigella is mediated by P., Frame, M. C. and Brunton, V. G. (2006). Src- filopodial actin filaments does not suggest the bacterial protein IcsA/VirG, which is dependent phosphorylation of Scar1 promotes its association with the Arp2/3 complex. Cell Motil. a role of activation of the Arp2/3 complex localised in a polarised manner on the Cytoskeleton 63, 6-13. in their formation. One alternative bacterial surface. IcsA/VirG recruits and Bear, J. E., Rawls, J. F. and Saxe, C. L., 3rd (1998). hypothesis is that SCAR/WAVE proteins activates host N-WASP by mimicking SCAR, a WASP-related protein, isolated as a suppressor of receptor defects in late Dictyostelium development. J. induce filopodia after branched actin Cdc42, which can bind to the regulatory Cell Biol. 142, 1325-1335. 2578 Journal of Cell Science 122 (15)

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Toca-1 driven by assembly and disassembly of actin filaments. available in the online version of this article mediates Cdc42-dependent actin nucleation by activating Cell 112, 453-465. at jcs.biologists.org. The JPEG images can the N-WASP-WIP complex. Cell 118, 203-216. Pollitt, A. Y. and Insall, R. H. (2008). Abi mutants in be downloaded for printing or used as Ibarra, N., Blagg, S. L., Vazquez, F. and Insall, R. H. Dictyostelium reveal specific roles for the SCAR/WAVE slides. (2006). Nap1 regulates Dictyostelium cell motility and complex in cytokinesis. Curr. Biol. 18, 203-210.