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

Author

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  • Marte Sneeggen

    (University of Oslo
    Oslo University Hospital)

  • Nina Marie Pedersen

    (University of Oslo
    Oslo University Hospital)

  • Coen Campsteijn

    (University of Oslo)

  • Ellen Margrethe Haugsten

    (University of Oslo
    Oslo University Hospital)

  • Harald Stenmark

    (University of Oslo
    Oslo University Hospital)

  • Kay Oliver Schink

    (University of Oslo
    Oslo University Hospital)

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.

Suggested Citation

  • Marte Sneeggen & Nina Marie Pedersen & Coen Campsteijn & Ellen Margrethe Haugsten & Harald Stenmark & Kay Oliver Schink, 2019. "WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling," Nature Communications, Nature, vol. 10(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10794-w
    DOI: 10.1038/s41467-019-10794-w
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    Cited by:

    1. Kay Oliver Schink & Kia Wee Tan & Hélène Spangenberg & Domenica Martorana & Marte Sneeggen & Virginie Stévenin & Jost Enninga & Coen Campsteijn & Camilla Raiborg & Harald Stenmark, 2021. "The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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