Cortactin in cell migration and cancer at a glance

Abstract

The actin-nucleation-promoting factor cortactin has emerged not only as a crucial regulator of actin cytoskeletal dynamics, but also as a key player in aggressive cancers (Buday and Downward, 2007; Weaver, 2008). Cortactin was first identified as a prominent substrate of the Src nonreceptor tyrosine kinase. Its name was derived from the observation that cortactin localizes to cortical actin structures (Wu et al., 1991). Since then, cortactin has been recognized for its association with cancer progression. Amplification of the gene that encodes cortactin (CTTN) and the resulting overexpression of cortactin protein have been observed in 15% of primary metastatic breast carcinomas and in nearly 30% of head and neck squamous cell carcinomas (Akervall et al., 1995; Buday and Downward, 2007). Overexpression of cortactin has also been linked to invasive cancers, including melanoma, colorectal cancer and glioblastoma, making cortactin an important biomarker for invasive cancers (Hirakawa et al., 2009; Kirkbride et al., 2011; Rothschild et al., 2006; Weaver, 2008; Xu et al., 2010).Much research on cortactin in the past decade has focused on mechanistically dissecting its role in cellular migration and invasion. Early on, cortactin was shown to bind filamentous (F)-actin (Wu and Parsons, 1993). This was followed by the discovery that cortactin is a nucleation-promoting factor (NPF) that binds and activates the Arp2/3 complex – a seven-subunit complex that is responsible for the formation of branched F-actin – revealing a direct mechanism for regulating the polymerization of actin during cell motility (Goley and Welch, 2006; Higgs and Pollard, 2001; Uruno et al., 2001; Weaver et al., 2001; Weed et al., 2000). The ability of cortactin to bind several cytoskeletal proteins through its C-terminal SH3 domain links this protein to numerous processes, including endocytosis, lamellipodial protrusion and directed cell migration (Ammer and Weed, 2008). More recent studies have focused on the role of post-translational modifications (PTMs) of cortactin, including phosphorylation and acetylation, as a means to regulate binding to actin, activation of the Arp2/3 complex and recruitment of cortactin-binding partners through interactions with Src homology 2 (SH2) domains. Importantly, cortactin has a central role in the development and maturation of invadopodia, which are actin-driven protrusive structures in invasive cancer cells that degrade the extracellular matrix (Weaver, 2008; Yamaguchi and Condeelis, 2007). This Cell Science at a Glance article focuses on how cortactin functions in cell migration and cancer-cell metastasis, and how it is regulated during these processes.Cortactin was initially shown to colocalize with cortical F-actin at the cell periphery (hence the name cortactin), suggestive of interactions with the actin cytoskeleton (Wu et al., 1991). Early sequence analysis and binding studies identified six central ‘cortactin repeats’ and demonstrated that the fourth repeat is required for direct binding to F-actin (Weed et al., 2000; Wu and Parsons, 1993). Structure prediction, circular dichroism and crosslinking studies suggest that the cortactin repeats are unstructured in solution and transition to a more stable conformation upon F-actin binding, which is in agreement with electron-microscopy models, but not necessarily with other molecular dynamics modeling (Pant et al., 2006; Shvetsov et al., 2009; Zhang et al., 2007). Regulation of F-actin binding might occur through alternative splicing within this region, as some splice variants show decreased affinity for F-actin (van Rossum et al., 2003). Structural analysis of cortactin so far has yielded diverse information. Single-particle electron microscopy images depict cortactin as having an elongated conformation, whereas small-angle X-ray scattering analysis suggests a more globular shape (Cowieson et al., 2008; Weaver et al., 2002). Sequence and functional analysis have elucidated the basic domain structure of cortactin, including an N-terminal acidic (NTA) region, which binds and activates the Arp2/3 complex, actin-binding repeats, multiple phosphorylation sites and a C-terminal SH3 domain (Ammer and Weed, 2008; Buday and Downward, 2007).The identification of cortactin SH3-domain-binding partners has provided important insights into how cortactin regulates distinct cellular processes. The cortactin SH3 domain interacts with the adhesion-complex protein zona occludens protein 1 (ZO-1) (Hirakawa et al., 2009; Katsube et al., 1998). Cortactin has also been shown to act downstream of E-cadherin activated by Src kinase and is required for actin polymerization at these cell–cell adhesions (Helwani et al., 2004; Ren et al., 2009). Although not shown to be a direct interaction, cortactin colocalizes with Syk kinase at sites of cell–cell contact, where Syk can phosphorylate cortactin (Zhang et al., 2009a). Cortactin-stimulated actin polymerization might increase the stren