期刊
JOURNAL OF CELL BIOLOGY
卷 199, 期 3, 页码 527-544出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201203025
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资金
- Cancer Research UK
- Medical Research Council UK [G117/569]
- Association for International Cancer Research [11-0119]
- MRC [G117/569, G1000419] Funding Source: UKRI
- Cancer Research UK [15672, 15673] Funding Source: researchfish
- Medical Research Council [G1000419, G117/569] Funding Source: researchfish
- Worldwide Cancer Research [11-0119] Funding Source: researchfish
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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