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bioRxiv · 10.1101/299610

WDFY2 restrains matrix metalloprotease secretion and cell invasion by retention of VAMP3 in endosomal tubules

Sneeggen, M.·Pedersen, N. M.·Campsteijn, C.·Haugsten, E. M.·Stenmark, H.·Schink, K. O.
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Abstract

The endosomal FYVE- and WD40-domain-containing protein WDFY2 has been assigned a function as tumour 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 a specific pool of 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 increased secretion of the matrix metalloprotease 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.

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Sneeggen, M., Pedersen, N. M., Campsteijn, C., Haugsten, E. M., Stenmark, H., Schink, K. O.. 2018-04-13. WDFY2 restrains matrix metalloprotease secretion and cell invasion by retention of VAMP3 in endosomal tubules. https://doi.org/10.1101/299610

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