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Nat Commun. 2019 Jun 28;10(1):2850. doi: 10.1038/s41467-019-10794-w.

WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling.

Author information

1
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, N-0379, Oslo, Norway.
2
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379, Oslo, Norway.
3
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317, Oslo, Norway.
4
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0379, Norway.
5
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, N-0379, Oslo, Norway. h.a.stenmark@medisin.uio.no.
6
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379, Oslo, Norway. h.a.stenmark@medisin.uio.no.
7
Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, N-0379, Oslo, Norway. Kay.Oliver.Schink@rr-research.no.
8
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, N-0379, Oslo, Norway. Kay.Oliver.Schink@rr-research.no.

Abstract

Cancer cells secrete matrix metalloproteinases to remodel the extracellular matrix, which enables them to overcome tissue barriers and form metastases. The membrane-bound matrix metalloproteinase MT1-MMP (MMP14) is internalized by endocytosis and recycled in endosomal compartments. It is largely unknown how endosomal sorting and recycling of MT1-MMP are controlled. Here, we show that the endosomal protein WDFY2 controls the recycling of MT1-MMP. WDFY2 localizes to endosomal tubules by binding to membranes enriched in phosphatidylinositol 3-phosphate (PtdIns3P). We identify the v-SNARE VAMP3 as an interaction partner of WDFY2. WDFY2 knockout causes a strong redistribution of VAMP3 into small vesicles near the plasma membrane. This is accompanied by increased, VAMP3-dependent secretion of MT1-MMP, enhanced degradation of extracellular matrix, and increased cell invasion. WDFY2 is frequently lost in metastatic cancers, most predominantly in ovarian and prostate cancer. We propose that WDFY2 acts as a tumor suppressor by serving as a gatekeeper for VAMP3 recycling.

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