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

X Yu, T Zech, L McDonald, EG Gonzalez, A Li… - Journal of cell …, 2012 - rupress.org
X Yu, T Zech, L McDonald, EG Gonzalez, A Li, I Macpherson, JP Schwarz, H Spence, K Futó…
Journal of cell biology, 2012rupress.org
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 …
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.
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