title: N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods.
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.
authors.affiliation: The Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, Scotland, UK.
authors.forename: Xinzi
authors.initials: X
authors.lastname: Yu
authors.forename: Tobias
authors.initials: T
authors.lastname: Zech
authors.forename: Laura
authors.initials: L
authors.lastname: McDonald
authors.forename: Esther Garcia
authors.initials: EG
authors.lastname: Gonzalez
authors.forename: Ang
authors.initials: A
authors.lastname: Li
authors.forename: Iain
authors.initials: I
authors.lastname: Macpherson
authors.forename: Juliane P
authors.initials: JP
authors.lastname: Schwarz
authors.forename: Heather
authors.initials: H
authors.lastname: Spence
authors.forename: Kinga
authors.initials: K
authors.lastname: Futó
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Ma
authors.forename: Ines M
authors.initials: IM
authors.lastname: Anton
authors.forename: Balázs
authors.initials: B
authors.lastname: Visegrády
authors.forename: Robert H
authors.initials: RH
authors.lastname: Insall
authors.forename: Karin
authors.initials: K
authors.lastname: Oien
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
authors.forename: Laura M
authors.initials: LM
authors.lastname: Machesky
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D055503:Protein Multimerization; D021381:Protein Transport; D011554:Pseudopodia / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D053511:Matrix Metalloproteinase 14