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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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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. |
format | Online Article Text |
id | pubmed-5576486 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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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