N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods

Yu, X. et al. (2012) N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. Journal of Cell Biology, 199(3), pp. 527-544. (doi:10.1083/jcb.201203025)

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Publisher's URL: http://dx.doi.org/10.1083/jcb.201203025

Abstract

Metastasizing tumor cells use matrix metalloproteases, such as the transmembrane collagenase MT1-MMP, together with actin-based protrusions, to break through extracellular matrix barriers and migrate in dense matrix. Here we show that the actin nucleation–promoting protein N-WASP (Neural Wiskott-Aldrich syndrome protein) is up-regulated in breast cancer, and has a pivotal role in mediating the assembly of elongated pseudopodia that are instrumental in matrix degradation. Although a role for N-WASP in invadopodia was known, we now show how N-WASP regulates invasive protrusion in 3D matrices. In actively invading cells, N-WASP promoted trafficking of MT1-MMP into invasive pseudopodia, primarily from late endosomes, from which it was delivered to the plasma membrane. Upon MT1-MMP’s arrival at the plasma membrane in pseudopodia, N-WASP stabilized MT1-MMP via direct tethering of its cytoplasmic tail to F-actin. Thus, N-WASP is crucial for extension of invasive pseudopods into which MT1-MMP traffics and for providing the correct cytoskeletal framework to couple matrix remodeling with protrusive invasion.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nixon, Mr Colin and Ma, Dr Yafeng and Zech, Mr Tobias and Machesky, Professor Laura and Blyth, Dr Karen and McDonald, Dr Laura and Oien, Dr Karin and Insall, Professor Robert and Schwarz, Ms Juliana and Yu, Dr Xinzi and Timpson, Dr Paul and MacPherson, Dr Iain and Norman, Professor James and Spence, Dr Heather
Authors: Yu, X., Zech, T., McDonald, L., Gonzalez, E. G., Li, A., MacPherson, I., Schwarz, J. P., Spence, H., Futo, K., Timpson, P., Nixon, C., Ma, Y., Anton, I. M., Visegrady, B., Insall, R. H., Oien, K., Blyth, K., Norman, J. C., and Machesky, L. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Cell Biology
Publisher:Rockefeller University Press
ISSN:0021-9525
ISSN (Online):1540-8140
Published Online:21 October 2012
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
620291Investigating the role of N-WASP in the development and metastasis of colorectal cancer (SCP3 Fellowship 2012)Laura MacheskyMedical Research Council (MRC)G1000419ICS - BEATSON INSTITUTE FOR CANCER RES.