Proteomics

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

ABSTRACT: The endosomal FYVE- and WD40-domain-containing protein WDFY2 has been assigned a function as tumor suppressor, but its functional mechanism has remained elusive. Here we have used confocal, widefield and super-resolution fluorescence microscopy to show that WDFY2 localizes to the base of retromer-containing endosomal tubules by a mechanism that involves recognition of highly curved membranes enriched in phosphatidylinositol 3-phosphate (PtdIns3P) by the WDFY2 FYVE domain. Affinity purification and mass spectrometry identified the v-SNARE VAMP3 as an interaction partner of WDFY2, and cellular knockout of WDFY2 caused a strong redistribution of VAMP3 into small vesicles near the plasma membrane. This was accompanied by VAMP3-dependent increased secretion of the matrix metalloproteinase MT1-MMP and 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman  

LAB HEAD: Tuula Nyman

PROVIDER: PXD013480 | Pride | 2019-07-02

REPOSITORIES: Pride

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

Sneeggen Marte M   Pedersen Nina Marie NM   Campsteijn Coen C   Haugsten Ellen Margrethe EM   Stenmark Harald H   Schink Kay Oliver KO  

Nature communications 20190628 1

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  ...[more]

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