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

Marte Sneeggen1,2, Nina Marie Pedersen1,2, Coen Campsteijn3

  • 1Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Montebello, N-0379, Oslo, Norway.

Nature Communications
|June 30, 2019
PubMed

Insights

The endosomal protein WDFY2 controls recycling of matrix metalloproteinase MT1-MMP. Loss of WDFY2 in cancer promotes metastasis by increasing MT1-MMP secretion and cell invasion.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Cancer cells utilize matrix metalloproteinases (MMPs) to degrade the extracellular matrix, facilitating metastasis.
  • The membrane-bound MMP, MT1-MMP (MMP14), is internalized and recycled via endosomal compartments, but its regulation is poorly understood.

Purpose of the Study:

  • To investigate the role of the endosomal protein WDFY2 in controlling the recycling of MT1-MMP.
  • To elucidate the molecular mechanisms by which WDFY2 regulates MT1-MMP trafficking and function.

Main Methods:

  • Immunofluorescence microscopy to determine protein localization.
  • Co-immunoprecipitation to identify interaction partners.
  • WDFY2 knockout cell models to assess functional consequences.
  • Analysis of extracellular matrix degradation and cell invasion assays.

Main Results:

  • WDFY2 localizes to endosomal tubules via binding to phosphatidylinositol 3-phosphate (PtdIns3P)-enriched membranes.
  • WDFY2 interacts with the v-SNARE VAMP3.
  • WDFY2 knockout leads to VAMP3 redistribution, increased MT1-MMP secretion, enhanced extracellular matrix degradation, and augmented cell invasion.
  • WDFY2 loss is prevalent in metastatic cancers, particularly ovarian and prostate cancer.

Conclusions:

  • WDFY2 acts as a crucial regulator of MT1-MMP recycling by controlling VAMP3 localization.
  • WDFY2 functions as a tumor suppressor by preventing excessive MT1-MMP secretion and subsequent cell invasion.
  • The loss of WDFY2 in metastatic cancers suggests its potential as a therapeutic target.

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