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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / physiology
  • Cell Line, Tumor
  • Cell Membrane
  • Exocytosis / physiology
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Matrix Metalloproteinases / genetics
  • Matrix Metalloproteinases / metabolism*
  • Microtubules
  • Neoplasm Invasiveness*
  • Phosphatidylinositol Phosphates / physiology
  • Protein Transport
  • Vesicle-Associated Membrane Protein 3 / genetics
  • Vesicle-Associated Membrane Protein 3 / metabolism*
  • rab4 GTP-Binding Proteins / genetics
  • rab4 GTP-Binding Proteins / metabolism


  • Actins
  • Intracellular Signaling Peptides and Proteins
  • Phosphatidylinositol Phosphates
  • VAMP3 protein, human
  • Vesicle-Associated Membrane Protein 3
  • WDFY2 protein, human
  • phosphatidylinositol 3-phosphate
  • Matrix Metalloproteinases
  • rab4 GTP-Binding Proteins