Cell Science at a Glance 1073

Actin-bundling proteins cellular structures, such as filopodia general, crosslinking proteins have two (spike-like protrusions), lamellipodia actin-binding sites, often because they in cancer progression at (sheet-like protrusions), stress fibers (elastic dimerise, and the location of actin-binding a glance contractile bundles), microvilli (finger-like sites determines the filament arrangement surface protrusions) and invadopodia and type of crosslinked structure formed. (invasive cell feet) (see Table 1 for a more Actin filaments are polar, with a fast- Richard P. Stevenson, Douwe complete list). Whereas the cytoskeleton is growing and a slow-growing end, and this Veltman and Laura M. Machesky* important in normal cellular function, it can polarity is maintained by a cycle of ATP The Beatson Institute for Cancer Research, Garscube be subverted in cancer cells and contributes hydrolysis (see Poster) (Pollard and Cooper, Estate, Switchback Rd, Bearsden, Glasgow G61 to changes in cell growth, stiffness, 2009). Bundling proteins can be selective 1BD, UK *Author for correspondence movement and invasiveness. We hereby about the orientation with which they bind to ([email protected]) give an overview of the role of actin- the filament, allowing the specific formation filament bundling in cellular structures and of bundles of either mixed or uniform Journal of Cell Science 125, 1073–1079 ß 2012. Published by The Company of Biologists Ltd discuss how alterations in the activity or polarity (see Poster). Bundling proteins are doi: 10.1242/jcs.093799 expression patterns of actin-bundling often modular and contain repeated actin- proteins could be linked to cancer initiation filament-binding domains (see Poster). For Cells use their cytoskeletons to move, or progression. example, the calponin-homology domain polarise, divide and maintain organisation Actin is one of the most abundant proteins (CH domain), gelsolin domain and spectrin within multicellular tissues. Actin is a highly in mammalian cells, and underpins the domain are used by many actin bundlers (see conserved essential building block of the compartmentalisation of cellular contents Poster). cytoskeleton that forms cables and struts, and motility. Filaments are assembled into which are constantly remodelled by more superstructures by actin-filament-bundling A role for actin-bundling proteins than 100 different actin-binding proteins. proteins. Some bundling proteins (e.g. fascin in metastasis The initiation of new actin filaments and and a-actinin) form parallel bundles, Metastatic cancer cells use actin bundles to their subsequent organisation is a key whereas others (e.g. filamin) form looser underpin protrusions that allow them to step in the development of specialised orthogonal meshworks (Bartles, 2000). In break away from a primary tumour and Journal of Cell Science

(See poster insert) Journal of Cell Science

Table 1. Clinical correlation between actin-bundling proteins and cancer 1074 Protein Structures and cell type Function Role in cancer References a-Actinin- Cellular protrusions, stress fibres, Crosslinks actin into parallel bundles by Expression in breast, ovary, pancreas, lung, astrocytoma (Fu et al., 2007; Hirooka et al., 2011; 1anda- lamellipodia, microvilli, forming dimers head to tail cancers. Associated with poor prognosis and tumour Honda et al., 2005; Honda et al., actinin-4 invadopodia of multiple cell types chemoresistance (ovary) 2004; Kikuchi et al., 2008; Menez et al., 2004; Welsch et al., 2009; Yamamoto et al., 2007; Yamamoto et al., 2009) Eplin Stress fibres of multiple cell types Actin filament bundling and side-binding Eplin downregulation correlates with progression and (Jiang et al., 2008; Sanders et al., 2011; metastasis in prostate cancer and eplin might be anti- Sanders et al., 2010; Zhang et al., 2010) angiogenic. Potential tumour suppressor in breast cancer Fascin Neurons, dendritic cells, endothelial cells Crosslinks actin into parallel bundles. Thought Significant independent prognostic indicator of poor (Machesky and Li, 2010) and cancer cells. Mainly in filopodia and to be a monomer with two actin-binding sites outcome in cancers of the liver, ovary, lung, pancreas, invadopodia, but also at cell–cell contacts colon, head and neck squamous cell carcinoma and brain Filamin-A Cell cortex, filopodia of many cell types Crosslinks into orthogonal gels Prostate cancer metastasis correlates with low nuclear and (Ai et al., 2011; Alper et al., 2009; high cytoplasmic filamin-A. Aberrant association of Anilkumar et al., 2003; Bedolla et al., filamin-A with the prion protein PrPA correlates with 2009; Burton et al., 2010; Castoria worse prognosis in pancreatic cancer. A secreted et al., 2011; Kwon et al., 2008; Li variant of filamin-A in the blood correlates with high- et al., 2010b; Li et al., 2010c; Li et al., grade astrocytomas and metastatic breast cancer 2009; Loy et al., 2003; Smith et al., 2007; Sy et al., 2010; Uramoto et al., 2010; Zhou et al., 2011) Formins Stress fibres and filopodia of multiple Actin nucleation and parallel bundling. Also Downregulation of formin-like-2 correlates with a poor (Liang et al., 2010) cell types interacts with microtubules prognosis in hepatocellular carcinoma. Higher expression correlates with tumour differentiation Mena Filopodia of many cell types and inva Related to VASP tetramerises and bundles actin Mena is overexpressed in breast cancers that show anti- (Di Modugno et al., 2004; Gurzu dopodia of cancer cells filaments while promoting elongation. Occurs tumour immune response. Expressed in colorectal polyps et al., 2008) in several splice forms and some [i.e. Mena with high dysplasia and in 80% of colorectal lesions (INV) and Mena11a] increase cellular invasion (n536) Myosin I Microvilli of intestinal epithelial cells Motor protein that connects membranes and No clinical studies and cortex of many cell types. actin and mediates transport of intracellular cargo vesicles, as well as attaching actin filaments in microvilli to the plasma membrane Myosin II Microvilli terminal web of intestinal Actin-based motor that also bundles actin. Interacts with S100A4 (also known as metastasin), which (Minamiya et al., 2005; Oslejskova epithelia and stress fibres of multiple Generates and/or maintains cortical tension, is heavily associated with cancer invasion and et al., 2008) cell types assembly of contractile structures. Cell body metastasis. Significant positive correlation between translocation and retraction of the posterior expression levels of myosin light chain kinase (which of the cell during migration activates myosin II) and likelihood of non-small cell lung cancer recurrence and metastasis T-plastin Microvilli of epithelial and mesenchymal Crosslinks F-actin into straight bundles T-plastin expression is enhanced in cisplatin-resistant (Hisano et al., 1996) (T-fim- cells human cancer cell lines (5) 125 Science Cell of Journal brin) L-plastin Microvilli of haematopoietic cells and Crosslinks F-actin into straight bundles 68% of epithelial carcinomas investigated and 53% of (Delanote et al., 2005; Foran et al., (L- malignant human cells of non-haema non-epithelial mesenchymal tumours examined 2006; Yuan et al., 2010) Fimbrin) topoietic origin expressed L-plastin. L-plastin expression correlates positively with colorectal cancer stage and severity Spectrin Microvilli and terminal web of intestinal Crosslinks actin into orthogonal networks by Reduced expression of spectrin associated with poor (Baek et al., 2011; Jiang et al., 2010; (Fodrin) epithelial cells and cell cortex of many forming tetramers. Forms a scaffold for prognosis in pancreatic cancer and progression in Kitisin et al., 2007; Maeda et al., cell types signalling complexes and keeps SMAD3 or hepatocellular cancer. Spectrin contributes to platinum 2011; Simpson and Page, 1992; SMAD4 inhibited. Possible tumour suppres chemotherapy resistance Sormunen et al., 1994; Sormunen sor and regulates cell polarity. Has also been et al., 1999; Thenappan et al., 2009; proposed to be a differentiation marker in Tuominen et al., 1996; Younes et al., colonic neoplasia 1989) Supervillin Stress fibres and focal adhesions of Actin bundling into parallel bundles Androgen receptor co-regulator that might be important in (Sampson et al., 2001; Wulfkuhle multiple cell types. Implicated in androgen-dependent prostate cancer et al., 1999) nuclear architecture Villin Epithelial cells of the gastrointestinal Crosslinks filaments in low Ca2+ and severs Expression altered in Barrett’s oesophagus, bladder (Sampson et al., 2001; Shi et al., 2008; tract that possess brush border microvilli filaments at high Ca2+ cancer, colorectal and intestinal cancer Younes et al., 1989; Zhang et al., 2007) Journal of Cell Science 125 (5) 1075

invade through the surrounding tissue. After Cortex mechanical strength and signalling scaffolds travelling in the vasculature or lymphatic Underneath the plasma membrane lies close to membranes (Popowicz et al., 2006) system, they exit into a new niche and seed a a meshwork of actin filaments and (see Poster). Filamins are mechanosensors, new tumour, often after lying dormant for crosslinking proteins termed the cortex (see and regulate transcription, membrane months or years (Hanahan and Weinberg, Poster). A strong cortical attachment to the trafficking, ion channel function, adhesion 2011). During metastasis, cells adapt their plasma membrane that is balanced by and receptor-mediated signalling (Popowicz motility and adhesive capacity to suit their contractility between actin and myosin et al., 2006). For example, filamin binds to environment, in much the same way as promotes protrusive motility, which is often the androgen receptor in a complex with embryonic cells do during morphogenesis referred to as ‘mesenchymal’. By contrast, a b1 integrin, and modulates cell-motility (recently reviewed by Hanahan and weaker attachment of the cytoskeleton to the responses downstream of androgen Weinberg, 2011; Roussos et al., 2011b). cortex than the force of actin- and myosin- signalling, which could drive invasion in The actin cytoskeleton serves as a based contractility promotes blebs, which prostate cancer (Castoria et al., 2011; Loy scaffold for signalling, a connection with are detachments between the cortex and et al., 2003) (see Poster). Filamins also form the extracellular environment and a membrane, leading to bleb-based motility a same complex with a pro-prion protein PrP mechanosensor. However, there is no (Friedl and Wolf, 2010). Modulation of in pancreatic cancer to give cancer cells a general rule whether actin bundling cortical stiffness thus changes how cells growth advantage (Sy et al., 2010), and promotes or inhibits cancer metastasis; move in different environments. The this same complex might contribute to rather, cancer cells can adjust the extent of cortex also provides a scaffold for the progression of melanoma (Li et al., 2010c). actin bundling to alter their signalling, organisation of transmembrane receptors Filamin modulates hepatocyte growth factor growth, or adhesion and mechanical and glycoproteins into networks for receptor (HGFR, also known as the proto- properties and thus can be selected for effective signal transduction and coupling oncogene Met) signalling, which is crucial survival during various phases of tumour of mechanical stresses to signals. for many epithelial cancers to metastasise progression and metastatic spread. Typically, Non-muscle myosin IIa and myosin IIb (Zhou et al., 2011). Filamins might also mechanical stiffness is positively correlated are the main actin-based contractile myosin form part of the nuclear skeleton, where they with invasion and metastatic potential motors that crosslink actin filaments of interact with DNA repair complexes such as breast cancer type 1 susceptibility protein (Narumiya et al., 2009), but exceptions the cell cortex and regulate cell stiffness. (BRCA1) (Velkova et al., 2010) and with exist (Swaminathan et al., 2011). Phosphorylation of the myosin II light chain triggers the contractile activity of myosin II cell cycle progression proteins such as The actin cytoskeleton maintains the (Narumiya et al., 2009). High levels of the cyclin D1 (CCND1) (Zhong et al., 2010) compartmentalisation of cellular contents myosin kinase Rho-associated protein (also see Poster). Finally, a secreted variant and thus is a major determinant of cell kinase 1 (ROCK1) are associated with of filamin has been detected in the blood of polarity. Polarity is essential for normal poor survival in breast cancer patients patients with advanced metastatic breast tissue homeostasis, and when disrupted, (Lane et al., 2008) and correlate with poor cancer and astrocytomas, indicating that can lead to tumour promotion through the tumour differentiation, muscle invasion and filamin might have a prognostic value breakdown of cell–cell junctions and Journal of Cell Science lymph node metastasis in bladder cancer (Alper et al., 2009) (Table 1). to epithelial-to-mesenchymal transition (Kamai et al., 2003). One clinical study Spectrins (also called fodrins) are another (EMT) (reviewed by Royer and Lu, showed a positive correlation between class of important actin crosslinkers of the 2011). Cell divisions are also polarised myosin light chain kinase, which activates cell cortex, which have been implicated in within tissues, so if polarity is lost, tissue myosin II, with disease recurrence and cancer. In colorectal and pancreatic integrity can be compromised, resulting in metastasis in non-small cell lung cancer cancers, b2-spectrin binds to and regulates overgrowth, aberrant invasive behaviour (Minamiya et al., 2005). Better reagents for the activity of transcriptional activators and promotion of tumours (reviewed by the detection of active myosin II or specific SMAD3 and SMAD4 of the transforming Royer and Lu, 2011). Actin bundling enrichment of myosin II isoforms are growth factor beta (TGFb) signalling contributes to the polarity of epithelial needed for further clinical studies pathway. TGFb signalling normally acts cells by maintaining cell–cell adherens (Vicente-Manzanares et al., 2009). as a tumour suppressor of colorectal cancer junctions, tight junctions and microvilli, Tumours can also influence the by suppressing growth and promoting and to polarised membrane trafficking (see contractile properties of stromal cells, apoptosis, but its dysregulation through Poster). However, understanding of the such as fibroblasts (Gaggioli et al., 2007; loss of b2-spectrin inappropriately mechanism by which cells subvert actin Sanz-Moreno et al., 2008; Wyckoff et al., activates Wnt signalling and promotes bundling to succeed in metastasis is still 2006). Increased stromal cell contractility tumourigenesis (Jiang et al., 2010; very much emerging and represents an promotes increased matrix stiffness and Thenappan et al., 2009) (also see Poster). exciting area of future research. this has tumour-promoting properties Embryonic spectrin (also called embryonic (Samuel et al., 2011). Matrix stiffness liver fodrin, ELF) shows altered expression Actin-bundle-containing structures promotes increased integrin attachment, in some cancers (Table 1) and its loss in normal and cancer cells and signalling and activation of pro- causes deregulation of cyclin D1 and Below, we summarise a subset of the survival and growth signals such as aberrant cell cycle progression (Kitisin various cellular structures that rely on activation of focal adhesion kinase (FAK) et al., 2007). actin bundles for their integrity, and the (Frame et al., 2010). actin bundling proteins, which have Whereas myosin II forms parallel Cell–cell junction been implicated in cancer initiation or contractile bundles, filamin proteins are Epithelia are held together by adherens progression. long, hinged actin bundlers that provide junctions, which contain transmembrane 1076 Journal of Cell Science 125 (5)

cadherin receptors that interact different actin-bundling proteins: T-plastin front of tumours, and in vitro reduction of extracellularly with the cadherins of (also named T-fimbrin), villin and small fascin causes reduced motility and invasion neighbouring cells and intracellularly with espin (Bartles et al., 1998; Loomis et al., (Hashimoto et al., 2007; Hashimoto et al., the actin cytoskeleton (see Poster) 2003). Microvilli also contain the cortical 2005; Li et al., 2010a; Schoumacher et al., (reviewed by Etienne-Manneville, 2011). components spectrin and myosin II in the 2010). Formins (including the mDia Adherens junctions connect to the cell terminal web (actin meshwork) at their base proteins, see Poster) are also filopodial cortex and to actin filament bundles that (see Poster) (Brown and McKnight, 2010) proteins with both actin-nucleating and are held in place by actin-bundling proteins, and are bound to the apical surface by brush actin-bundling activity. The actin-binding such as a-actinin and myosin II (Etienne- border myosin I (McConnell and Tyska, FH2 domains of mDia1, mDia2 and mDia3 Manneville, 2011). When epithelial cells 2007). T-plastin is a monomeric protein, dimerise and can both nucleate and bundle become cancerous, adherens junctions highly expressed in the small intestine, that actin (Machaidze et al., 2010). Not much is break down, which frees b-catenin from crosslinks F-actin into straight bundles known about the role(s) of the mDia proteins cadherins to enter the nucleus and (Brown and McKnight, 2010; Delanote or indeed the other 12 mammalian formins activate transcriptional changes that lead et al., 2005). L-plastin (Table 1, also in cancer (Table 1) (Nurnberg et al., 2011). to endothelial–mesenchymal transition known as L-fimbrin) is normally only The Ena/VASP proteins (Mena, VASP (EMT) through the canonical Wnt present in haematopoietic cells; however, and Evl in mammals) comprise a family of signalling pathway (Heuberger and one study showed that it is expressed in proteins that promote actin polymerisation Birchmeier, 2010). Junctional breakdown more than half of epithelial carcinomas and bundling, and associate with filopodia also physically releases tumour cells, and non-epithelial mesenchymal tumours tips, as well as with lamellipodia, cadherin- based cell–cell contacts (Breitsprecher et al., allowing them to escape from the primary (Delanote et al., 2005). L-plastin expression 2008; Breitsprecher et al., 2011; Scott et al., tumour and invade the surrounding tissue further correlates with stage and severity of 2006) and focal adhesions (reviewed by Pula (see Poster). colorectal cancers and is considered a and Krause, 2008). Recently a splice variant a-Actinin-1 and a-actinin-4 localise to potential prognostic indicator (Foran et al., of Mena, termed MenaINV, was found to be cell–cell contacts (Gonzalez et al., 2001) 2006; Yuan et al., 2010). Villin mediates overexpressed in breast and colorectal where they regulate actin bundling and bundling, nucleation (initiation of new epithelial integrity. a-Actinin-4 binds to cancers (Di Modugno et al., 2004). Mena filaments), capping and severing of actin deficiency decreases invasion, metastasis and recruits the tight junction proteins filaments in a Ca2+-dependent manner junctional Rab13 binding protein (JRAB) and tumour progression in polyoma (Friederich et al., 1990), and is highly middle-T transgenic mouse models and and molecule interacting with CAS-like 2 expressed in adenocarcinomas originating impairs normal breast development (MICAL-L2) and thus participates in tight from epithelial cells of the intestinal tract (Roussos et al., 2011a; Roussos et al., junction formation (Nakatsuji et al., 2008). that bear brush border microvilli (Grone 2010; Roussos et al., 2011c). Tight junctions lie apical to adherens et al., 1986; Moll et al., 1987; Suh et al., junctions (see Poster) and maintain 2005). Small espin contributes to elongation Invadopodium impermeability of epithelial tissues. Loss Journal of Cell Science of microvilli from the barbed end of the Invadopodia are dynamic actin-rich of a-actinin-4 disrupts the integrity of tight actin bundle, but has not yet been membrane protrusions found only in junctions and has been associated with implicated in cancer. In malignant cells, invasive cancer cells (Weaver, 2006). They cancer invasion and metastasis (Nakatsuji an increased number of microvilli with contain a mixture of bundled and branched et al., 2008). However, in most studies, irregular morphology can correlate with actin (Schoumacher et al., 2010) and are high levels of a-actinin-4 correlate with metastatic status (Ren, 1991; Ren et al., used for matrix remodeling (see Poster). poor outcome or advanced disease (Honda 1990), but the significance of this is unclear. Podosomes are structurally and functionally et al., 1998; Honda et al., 2005; Honda et al., similar to invadopodia, but occur in 2004; Kikuchi et al., 2008; Menez et al., Filopodium hematopoietic cells, endothelial cells and 2004; Patrie et al., 2002; Weins et al., 2007; Filopodia are long, thin, actin-based Src-transformed fibroblasts (Murphy Welsch et al., 2009; Yamada et al., 2010; protrusions that promote cell migration and and Courtneidge, 2011). Invadopodia and Yamamoto et al., 2007; Yamamoto et al., contribute to cancer cell invasion (Mattila podosomes contain a number of actin- 2009), and the relevance of its role in tight and Lappalainen, 2008; Nurnberg et al., bundling proteins, including fascin (Li junction assembly for cancer thus remains 2011) (see Poster). The parallel actin- et al., 2010a; Schoumacher et al., 2010), a- unclear. Other functions of a-actinin-4, bundling protein fascin is found in actinin, formins and Ena/VASP proteins such as in leading edge protrusion (Honda filopodia, but is normally expressed in (see Poster) (Murphy and Courtneidge, et al., 1998) might contribute to metastasis cells derived from mesenchymal and 2011). The actin bundles are used for and further study is warranted. neural sources rather than epithelia protrusion into matrix and possibly for (Adams, 2004a; Adams, 2004b; Hashimoto delivery of endocytic cargo such as matrix Microvillus et al., 2011). Fascin expression is often metalloproteases (Murphy and Courtneidge, Microvilli are finger-like projections of the upregulated in epithelial cancers and is 2011). plasma membrane that increase the surface associated with invasion and metastasis area of cells to enhance absorption and (Machesky and Li, 2010). Fascin-mediated Stress fibres secretion. Intestinal brush-border microvilli actin bundle formation strengthens filaments Stress fibres are bundles of parallel actin contain a parallel actin bundle core made up and increases the lifetime of both filopodia filaments with mixed polarity along their of about 40 actin filaments of uniform and invasive protrusions (Li et al., 2010a). length (Cramer et al., 1997) (see Poster) and polarity that are crosslinked by at least three Fascin is highly expressed at the invasive myosin II motors that are crosslinked by Journal of Cell Science 125 (5) 1077

alternating zones of a-actinin and Ena/ Concluding remarks and future potential forked protein ortholog in brush border microvilli. J. Cell Biol. 143, 107-119. VASP proteins and anchored at their ends perspectives Bedolla, R. G., Wang, Y., Asuncion, A., Chamie, K., by focal adhesion proteins (see Poster). Cancer metastasis represents the most Siddiqui, S., Mudryj, M. M., Prihoda, T. J., Siddiqui, Stress fibres connect the cytoskeleton to the deadly aspect of most cancers and also J., Chinnaiyan, A. M., Mehra, R. et al. (2009). Nuclear versus cytoplasmic localization of filamin A in prostate extracellular matrix at focal adhesion sites, arguably one of the most exciting frontiers cancer: immunohistochemical correlation with metastases. where integrins span the plasma membrane for modern biomedical investigation. Clin. Cancer Res. 15, 788-796. and cluster to form large macromolecular Breitsprecher, D., Kiesewetter, A. K., Linkner, J., Tackling metastasis is a complex goal Urbanke, C., Resch, G. P., Small, J. V. and Faix, J. hubs of signalling and cytoskeletal proteins and the improvement of technologies to (2008). Clustering of VASP actively drives processive, (Wolfenson et al., 2009). Focal adhesions study tumour lineages and metastatic WH2 domain-mediated actin filament elongation. EMBO are mechanosensing signal-transducing J. 27, 2943-2954. spread are rapidly developing (e.g. Breitsprecher, D., Kiesewetter, A. K., Linkner, J., assemblies that reflect the interaction of a Campbell et al., 2010; Yachida et al., Vinzenz, M., Stradal, T. E., Small, J. V., Curth, U., cell with its stroma and relay survival 2010). But equally, as we find out more Dickinson, R. B. and Faix, J. (2011). Molecular and growth signals. a-Actinin-1 distributes mechanism of Ena/VASP-mediated actin-filament about how tumours evolve, we are also elongation. EMBO J. 30, 456-467. along stress fibres in a periodic fashion humbled by the staggering complexity of Brown, J. W. and McKnight, C. J. (2010). Molecular and binds a number of focal adhesion cancer and of the body. The actin model of the microvillar cytoskeleton and organization of constituents (Edlund et al., 2001), thereby the brush border. PLoS ONE 5, e9406. cytoskeleton represents a major network Burton, E. R., Gaffar, A., Lee, S. J., Adeshuko, F., connecting the actin cytoskeleton to the of proteins that impinge on motility, Whitney, K. D., Chung, J. Y., Hewitt, S. M., Huang, cell membrane. a-Actinin-4 is generally invasion, polarity, survival and growth of G. S., Goldberg, G. L., Libutti, S. K. et al. (2010). Downregulation of Filamin A interacting protein 1-like is found at the leading edges of motile cells normal cells, and as such is often subverted associated with promoter methylation and induces an in lamellipodia. a-Actinin (especially by tumour cells. We are just starting to invasive phenotype in ovarian cancer. Mol. Cancer Res. a-actinin-4) is implicated in multiple understand how tumours manipulate the Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A., Morsberger, tumours, including breast (Guvakova et al., cytoskeleton to gain advantage and to L. A., Latimer, C., McLaren, S., Lin, M. L. et al. 2002), ovarian (Yamamoto et al., 2009) uncover those key proteins that might (2010). The patterns and dynamics of genomic instability (where it is a prognostic indicator of poor be future targets against invasion and in metastatic pancreatic cancer. Nature 467, 1109-1113. Castoria, G., D’Amato, L., Ciociola, A., Giovannelli, P., outcome), pancreas (Kikuchi et al., 2008) metastasis. It seems unlikely that one Giraldi, T., Sepe, L., Paolella, G., Barone, M. V., and lung cancers (Menez et al., 2004) (see particular actin-binding protein will ever Migliaccio, A. and Auricchio, F. (2011). Androgen- Table 1). induced cell migration: role of androgen receptor/filamin rise above the rest as the most important A association. PLoS ONE 6, e17218. Epithelial protein lost in neoplasm (Eplin), target in metastasis, but rather, like signal Chin, Y. R. and Toker, A. (2010). The actin-bundling is another component of stress fibres; it has transduction networks, we will find hub protein palladin is an Akt1-specific substrate that regulates filament side-binding and bundling activity breast cancer cell migration. Mol. Cell 38, 333-344. proteins or key pathways that can promote Cramer, L. P., Siebert, M. and Mitchison, T. J. (1997). that is antagonistic toward Arp2/3 complex tumour progression and develop therapies Identification of novel graded polarity actin filament branching activity (Maul et al., 2003) and is aimed at these. bundles in locomoting heart fibroblasts: implications for downregulated during cancer progression the generation of motile force. J. Cell Biol. 136, 1287- 1305. (Table 1). Eplin contains a central LIM A high-resolution version of the poster is available for downloading in the online version of this article at Delanote, V., Vandekerckhove, J. and Gettemans, J. Journal of Cell Science domain flanked by two actin-filament- jcs.biologists.org. (2005). Plastins: versatile modulators of actin organization binding sites. Palladin is an in (patho)physiological cellular processes. Acta Pharmacol. Sin. 26, 769-779. immunoglobulin-repeat-containing protein References Di Modugno, F., Bronzi, G., Scanlan, M. J., Del Bello, that binds to actin filaments and serves as a Adams, J. C. (2004a). Fascin protrusions in cell D., Cascioli, S., Venturo, I., Botti, C., Nicotra, M. R., scaffold for other stress-fibre-associated interactions. Trends Cardiovasc. Med. 14, 221-226. Mottolese, M., Natali, P. G. et al. (2004). Human Mena Adams, J. C. (2004b). 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