Cortactin: a multifunctional regulator of cellular invasiveness

Abstract

Branched actin assembly is critical for a variety of cellular processes that underlie cell motility and invasion, including cellular protrusion formation and membrane trafficking. Activation of branched actin assembly occurs at various subcellular locations via site-specific activation of distinct WASp family proteins and the Arp2/3 complex. A key branched actin regulator that promotes cell motility and links signaling, cytoskeletal and membrane trafficking proteins is the Src kinase substrate and Arp2/3 binding protein cortactin. Due to its frequent overexpression in advanced, invasive cancers and its general role in regulating branched actin assembly at multiple cellular locations, cortactin has been the subject of intense study. Recent studies suggest that cortactin has a complex role in cellular migration and invasion, promoting both on-site actin polymerization and modulation of autocrine secretion. Diverse cellular activities may derive from the interaction of cortactin with site-specific binding partners.

Figure 1

Regulation of cellular motility by branched actin and cortactin. Cell motility requires coordination of several processes, including protrusion of the leading edge lamellipodium, adhesion, contraction of actin bundles, and retraction of the rear of the cell. Depicted in the zoomed panels are mechanisms by which cortactin may regulate motility, including: promoting lamellipodial persistence, focal adhesion assembly, cellular signaling and secretion of autocrine factors

Figure 2

Cortactin domain structures. Schematic diagram of key cortactin domains and binding partners. The following abbreviations are used: NT A, N-terminal acidic domain and SH3, Src homology 3 domain. Proteins whose interaction with cortactin has been narrowed down to a particular domain are represented in the same color as the domain on cortactin. Interacting proteins shown in yellow bind the amino terminus of cortactin, which constitute the NT A + repeats domains. Amino acids that are essential for the interaction with key cortactin binding proteins, including W22 for interaction with Arp2/3 and W525 for interactions within the SH3 domain, are shown. The kinases known to phosphorylate cortactin are found above the respective sites they have been shown (or hypothesized) to phosphorylate.

Figure 3

Model of cortactin function at invadopodia. Cortactin is thought to contribute to two major processes in invadopodia: (1) actin polymerization for initiation and/or maturation of invadopodia via activation of N-WASp via Nck, activation of cdc42 via Fgd1, and coactivation of Arp2/3 complex and (2) vesicular trafficking of matrix metalloproteinases to invadopodia via either regulation of post-Golgi trafficking or vesicle capture at invadopodia. Once ECM-degradation is established at invadopodia, they may become longer-lived due to positive feedback.