N-WASP Coordinates the Delivery and F-actin Mediated Reversible Capture of MT1-MMP at Invasive Pseudopods to Drive Breast Cancer Cell Invasion

Zech, T. et al. (2012) N-WASP Coordinates the Delivery and F-actin Mediated Reversible Capture of MT1-MMP at Invasive Pseudopods to Drive Breast Cancer Cell Invasion. 2012 American Society for Cell Biology Annual Meeting, San Francisco, CA, USA, 15-19 Dec 2012. p. 2076. (doi: 10.1091/mbc.e12-10-0757)

Abstract

Metastasizing tumor cells use matrix metalloproteases, such as the transmembrane collagenase MT1-MMP, together with actin based protrusion, to break through extracellular matrix barriers and migrate in dense matrix. Here we show that the actin nucleation factor NWASP is upregulated in breast cancer and that N-WASP has a pivotal role in mediating the assembly of elongated pseudopodia instrumental in matrix degradation. In actively invading cells N-WASP promotes trafficking of MT1-MMP from late endosomes to “actin-hotspots” in invasive pseudopodia. These actin rich domains on pseudopods in matrix are shown to mature from adhesion sites to degradative foci by actively sequestrating MT1-MMP via direct actin binding of the metalloprotease. This clustering of MT1-MMP is shown to be required to achieve matrix degradation and N-WASP mediated actin polymerization is a prerequisite for this process. We demonstrate regulation of the MT1-MMP interactions with actin networks by phosphorylation. Our results thus suggest a new integrated model of regulated actin mediated receptor targeting in 3D cancer cell invasion.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Machesky, Professor Laura
• Authors: Zech, T., Yu, X., MacDonald, L., Gonzalez, E.G., MacPherson, I., Insall, R., Anton, I., Oien, K., Blyth, K., Norman, J.C., and Machesky, L.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• ISSN: 1059-1524