A new role for cortactin in invadopodia: Regulation of protease secretion

Abstract

Invadopodia are actin-dependent organelles that function in the invasion and remodeling of the extracellular matrix (ECM) by tumor cells. Cortactin, a regulator of the Arp2/3 complex, is of particular importance in invadopodia function. While most of the focus has been on the possible role of cortactin in actin assembly for direct formation of actin-rich invadopodia puncta, our recent data suggest that the primary role of cortactin in invadopodia is to promote protease secretion. In this manuscript, we review our previous work and present new data showing that cortactin is essential for both the localization of key invadopodia matrix metalloproteinases (MMPs) to actin-positive puncta at the cell-ECM interface and for ECM degradation induced by overexpression of MT1-MMP-GFP. Based on these data and results from the literature, we propose potential mechanisms by which cortactin may link vesicular trafficking and dynamic branched actin assembly to regulate protease secretion for invadopodia-associated ECM degradation.

Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation

“…Future studies should address whether WT Src is necessary to control trafficking to, or activation of MT1-MMP at invadopodia. These studies are further warranted because it has been proposed that a major role of cortactin in invadopodia function involves the targeting and delivery of MMPs to invadopodia to enhance ECM degradation (Clark and Weaver, 2008;Clark et al, 2007).…”

“…Cortactin is an actin-binding protein that is phosphorylated by Src kinase (Head et al, 2003), and is a core invadopodia component. Knockdown of cortactin expression results in decreased invadopodia formation (Artym et al, 2006; Oncogenic Src requires a wild-type counterpart to regulate invadopodia maturation Laura C. Kelley 1 al., 2007) and MMP secretion (Clark and Weaver, 2008;Clark et al, 2007), whereas phosphorylation of cortactin is important for regulation of matrix degradation at invadopodia .…”

Matrix invasion by tumour cells: a focus on MT1-MMP trafficking to invadopodia

“…Furthermore, MT1-MMP accumulates at invadopodia, where it is required for focal pericellular degradation of the ECM (Artym et al, 2006;Clark and Weaver, 2008;Nakahara et al, 1997;SakuraiYageta et al, 2008;Steffen et al, 2008).…”

“…Most interestingly, MT1-MMP and MMP-2 were shown to accumulate at the invasive front of tumours (Hofmann et al, 2003;Ueno et al, 1997). Moreover, MT1-MMP (and secreted MMP-2 and MMP-9) are enriched at invadopodia, which are specialized actin-based membrane protrusions that occur in invasive tumoural and transformed cells grown on ECM, and can degrade the matrix (Bowden et al, 1999;Buccione et al, 2004;Chen, 1989;Clark and Weaver, 2008;Gimona et al, 2008;Linder, 2007;Nakahara et al, 1997;Stylli et al, 2008). Invadopodia are small dot-shaped, F-actin-rich plasma-membrane extensions that are enriched in cell-matrix adhesion molecules, tyrosine kinases (including Src), tyrosine-phosphorylated proteins, actin-assembly regulators and matrix proteases Gimona et al, 2008;Linder, 2007;Stylli et al, 2008).…”

The interplay between the proteolytic, invasive, and adhesive domains of invadopodia and their roles in cancer invasion

“…their secretion. 36,39,49 The adhesion machinery is also thought to play a role in invadopodia maturation and matrix degradation: β1 integrin co-clusters with MT1-MMP at sites of interaction with collagen fibers along the cell's leading edge. 50,51 In addition, inhibition of integrin-mediated adhesion reduces recruitment of IQGAP to invadopodia, as well as matrix degradation.…”