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Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells

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...

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Autores principales: van Veen, Michiel, Matas-Rico, Elisa, van de Wetering, Koen, Leyton-Puig, Daniela, Kedziora, Katarzyna M, De Lorenzi, Valentina, Stijf-Bultsma, Yvette, van den Broek, Bram, Jalink, Kees, Sidenius, Nicolai, Perrakis, Anastassis, Moolenaar, Wouter H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576486/
https://www.ncbi.nlm.nih.gov/pubmed/28849762
http://dx.doi.org/10.7554/eLife.23649
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author van Veen, Michiel
Matas-Rico, Elisa
van de Wetering, Koen
Leyton-Puig, Daniela
Kedziora, Katarzyna M
De Lorenzi, Valentina
Stijf-Bultsma, Yvette
van den Broek, Bram
Jalink, Kees
Sidenius, Nicolai
Perrakis, Anastassis
Moolenaar, Wouter H
author_facet van Veen, Michiel
Matas-Rico, Elisa
van de Wetering, Koen
Leyton-Puig, Daniela
Kedziora, Katarzyna M
De Lorenzi, Valentina
Stijf-Bultsma, Yvette
van den Broek, Bram
Jalink, Kees
Sidenius, Nicolai
Perrakis, Anastassis
Moolenaar, Wouter H
author_sort van Veen, Michiel
collection PubMed
description 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.
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spelling pubmed-55764862017-08-31 Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells van Veen, Michiel Matas-Rico, Elisa van de Wetering, Koen Leyton-Puig, Daniela Kedziora, Katarzyna M De Lorenzi, Valentina Stijf-Bultsma, Yvette van den Broek, Bram Jalink, Kees Sidenius, Nicolai Perrakis, Anastassis Moolenaar, Wouter H eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2017-08-29 /pmc/articles/PMC5576486/ /pubmed/28849762 http://dx.doi.org/10.7554/eLife.23649 Text en © 2017, van Veen et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
van Veen, Michiel
Matas-Rico, Elisa
van de Wetering, Koen
Leyton-Puig, Daniela
Kedziora, Katarzyna M
De Lorenzi, Valentina
Stijf-Bultsma, Yvette
van den Broek, Bram
Jalink, Kees
Sidenius, Nicolai
Perrakis, Anastassis
Moolenaar, Wouter H
Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title_full Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title_fullStr Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title_full_unstemmed Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title_short Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells
title_sort negative regulation of urokinase receptor activity by a gpi-specific phospholipase c in breast cancer cells
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576486/
https://www.ncbi.nlm.nih.gov/pubmed/28849762
http://dx.doi.org/10.7554/eLife.23649
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