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

Marte Sneeggen, Nina Marie Pedersen, Coen Campsteijn, Ellen Margrethe Haugsten, Harald Stenmark () and Kay Oliver Schink ()
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Marte Sneeggen: University of Oslo
Nina Marie Pedersen: University of Oslo
Coen Campsteijn: University of Oslo
Ellen Margrethe Haugsten: University of Oslo
Harald Stenmark: University of Oslo
Kay Oliver Schink: University of Oslo

Nature Communications, 2019, vol. 10, issue 1, 1-20

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10794-w

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