Biology subjects

Haugsten, E. M.

Publications and source records attributed to Haugsten, E. M..

2 recordsLinked to original sources

bioRxiv2018

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

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.

cell biology↗

bioRxiv2017

The phosphatase PTPRG controls FGFR1 activity and influences sensitivity to FGFR kinase inhibitors

FGFR1 represents an important target for precision medicine and a detailed molecular understanding of the target is important in order to increase the efficacy of FGFR inhibitors. We have here applied proximity labelling of FGFR1 in an osteosarcoma cell line to identify determinants of FGFR1 activity. Many known FGFR interactors were identified (e.g. FRS2, PLC{gamma}, RSK2, SHC4, SRC), but the data also suggested novel determinants. A strong hit in our screen was the tyrosine phosphatase PTPRG. We show that PTPRG and FGFR1 interact and colocalize at the plasma membrane where PTPRG directly dephosphorylates activated FGFR1. We further show that osteosarcoma cell lines depleted for PTPRG display increased FGFR activity and are hypersensitive to stimulation by FGF1. In addition, PTPRG depletion elevated cell growth and negatively affected the efficacy of FGFR kinase inhibitors. Thus, PTPRG may have future clinical relevance by being a predictor of outcome after FGFR inhibitor treatment.

cell biology↗