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oai:riuma.uma.es:10630/336452026-02-03T10:49:38Zcom_10630_2254col_10630_37953

00925njm 22002777a 4500 dc van Veen, Michiel author Matas-Rico, Elisa author van de Wetering, Koen author Leyton-Puig, Daniela author Kedziora, Katarzyna M author De Lorenzi, Valentina author Stijf-Bultsma, Yvette author van den Broek, Bram author Jalink, Kees author Sidenius, Nicolai author Perrakis, Anastassis author Moolenaar, Wouter H author 2017-08-29 The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in breast cancer cells, resulting in a less transformed phenotype, it slows tumor growth in a xenograft model and correlates with prolonged survival in patients. Our results establish GDE3 as a negative regulator of the uPAR signaling network and, furthermore, highlight GPI-anchor hydrolysis as a cell-intrinsic mechanism to alter cell behavior. Michiel van VeenElisa Matas-RicoKoen van de WeteringDaniela Leyton-PuigKatarzyna M KedzioraValentina De LorenziYvette Stijf-BultsmaBram van den BroekKees JalinkNicolai SideniusAnastassis PerrakisWouter H Moolenaar (2017) Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells eLife 6:e23649. https://hdl.handle.net/10630/33645 10.7554/eLife.23649. Receptores celulares Citología Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells