How do invadopodia degrade the extracellular matrix?2018-02-06T10:45:43+08:30

How do invadopodia degrade the extracellular matrix?

The main function attributed to invadopodia is that of extracellular matrix (ECM) degradation, facilitated by the secretion of proteases. Maintenance of this process requires the delivery of new proteases from the Golgi, which is conveniently positioned in close proximity to invadopodia [1]. Indeed, the treatment of cells with Brefeldin A, an inhibitor of ER (endoplasmic reticulum) to Golgi transport, has been shown to prevent ECM degradation by invadopodia [2]. The Ena/VASP family protein, Mena, is also implicated in this process. More specifically the MenaINV isoform that favors cancer cell invasiveness by promoting the stabilization of invadopodia and enhancing their ECM-degrading activity [3][4].

ECM degradation itself is carried out by a variety of secreted matrix metalloproteinases (MMPs) and serine proteases. Currently over 25 different MMPs have been identified that together have the potential to degrade the entire ECM [5]. Of all the MMPs, MMP14 (also known as MT1-MMP), is considered to be the major regulator of invadopodia-mediated ECM degradation across several cell models [6]. MMP docking has been shown to be essential for ECM degradation in melanoma cells, with knock-down [7] or overexpression [5] showing a decrease or increase in invadopodial activity, respectively. Cortactin, commonly known as a weak activator of the actin nucleator Arp2/3, also has a role to play in MMP secretion and ECM degradation [6].

Cortactin accumulation has been shown to precede MMP accumulation at the tips of invadopodia and has been suggested to regulate their secretion [7]. This cortactin-dependent maturation process has been shown to be dependent on the activity of LIM kinases [8].

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