ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion.
Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1-matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase-interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein-dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin-dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6-JIP-MT1-MMP-dynein-dynactin-kinesin-1 axis promoting an invasive phenotype of breast cancer cells.
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France University Pierre et Marie Curie Paris 06, 75000 Paris, France.
Valentina
V
Marchesin
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Antonio
A
Castro-Castro
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Catalina
C
Lodillinsky
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Alessia
A
Castagnino
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Joanna
J
Cyrta
Department of Translational Research, Residual Tumor and Response to Treatment Laboratory, Institut Curie, 75248 Paris, France Institut National de la Sante et de la Recherche Médicale, Unite Mixte de Recherche 932 Immunity and Cancer, Institut Curie, 75248 Paris, France Department of Surgery, Institut Curie, 75248 Paris, France.
Hélène
H
Bonsang-Kitzis
Department of Pathology, Institut Curie, 75248 Paris, France.
Laetitia
L
Fuhrmann
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Marie
M
Irondelle
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Elvira
E
Infante
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France.
Guillaume
G
Montagnac
Department of Translational Research, Residual Tumor and Response to Treatment Laboratory, Institut Curie, 75248 Paris, France Institut National de la Sante et de la Recherche Médicale, Unite Mixte de Recherche 932 Immunity and Cancer, Institut Curie, 75248 Paris, France Department of Surgery, Institut Curie, 75248 Paris, France.
Fabien
F
Reyal
Department of Pathology, Institut Curie, 75248 Paris, France.
Anne
A
Vincent-Salomon
PSL Research University, Institut Curie, 75248 Paris, France Membrane and Cytoskeleton Dynamics, Centre National de la Recherche Scientifique, Unite Mixte de Recherche 144, 75248 Paris, France philippe.chavrier@curie.fr.
Philippe
P
Chavrier
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering; D018874:Spheroids, Cellular; D064726:Triple Negative Breast Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000089982:ADP-Ribosylation Factor 6; D048868:Adaptor Proteins, Signal Transducing; C087415:KIF3A protein, human; C488101:KIF5B protein, human; C485750:MAPK8IP3 protein, human; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C111047:SPAG9 protein, human; C549919:WASH protein, human; D003094:Collagen; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D016547:Kinesins; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human