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Actin-Bundling Proteins in Cancer Progression at a Glance

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Actin-Bundling Proteins in Cancer Progression at a Glance 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 Journal of Cell Science 125 (5) 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
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