Cortactin in tumor invasiveness

Abstract

Cortactin is a cytoskeletal protein and src kinase substrate that is frequently overexpressed in cancer. Animal studies suggest that cortactin overexpression increases tumor aggressiveness, possibly through promotion of tumor invasion and metastasis. Recently, many studies have documented a role for cortactin in promoting cell motility and invasion, including a critical role in invadopodia, actin rich-subcellular protrusions associated with degradation of the extracellular matrix by cancer cells. Here, I review the evidence and potential mechanisms for cortactin as a critical mediator of tumor cell invasion.

Figure 1. Cortactin domain structure and binding partners

Cortactin structure and domains is depicted in bright blue. Actin filaments (F-actin) is in light blue. Cortactin binding partners are indicated by labeling within the yellow boxes. The N-terminus of cortactin is composed of the N-terminal acidic (NTA) domain and the cortactin repeats (each repeat is represented by a numbered diamond) region. These two domains are notable for binding Arp2/3 complex and F-actin, respectively. The repeat is depicted binding to F-actin, because it is essential for that interaction; however, the other repeat regions contribute to binding affinity [18]. In the C-terminus, the proline rich region contains well-characterized serine and tyrosine phosphorylation sites. SS indicates the Erk S405 and S418 sites, whereas YYY indicates the Y421, Y466, and Y488 sites that are phosphorylated by src and the other tyrosine kinases indicated in the yellow box. Some of the cytoskeletal, membrane trafficking, and signaling proteins that bind to the SH3 domain are indicated in the yellow box below it. Biochemical activities regulated by the N-terminus and C-terminus are indicated at the bottom of the figure. For a full listing of binding partners, see Table 1. Illustration by Emily Clark, Ph.D.

Figure 2. Cortactin is a strong invadopodia marker

Primary head and neck squamous carcinoma cells were isolated from tumors and plated, without previous culture, on coverslips coated with a thin film of crosslinked gelatin overlaid with FITC-Fibronectin, as previously described [48]. After 36 h, cells were fixed and immunostained with 4F11 mAb against cortactin, followed by an anti-mouse AlexaFluor-633 secondary antibody (Invitrogen) (blue in merge), and stained for actin filaments with rhodamine-phalloidin (red in merge). Degraded areas of ECM are evident as dark holes in the FITC-Fibronectin (green in merge) image. An arrow points to an example invadopodia in each of the separated and merged images. Note the colocalization of cortactin and actin punta with focal degradation of the ECM. Arrowheads in the cortactin image point out cortactin localization to other sites of branched actin assembly: lamellipodia at the edge of the cell and cell-cell junctions. Scale bar = 10 µm. Unpublished data by Emily Clark, Ph.D.