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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/23649 |
| _version_ | 1818019762946441216 |
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| author | Michiel van Veen Elisa Matas-Rico Koen van de Wetering Daniela Leyton-Puig Katarzyna M Kedziora Valentina De Lorenzi Yvette Stijf-Bultsma Bram van den Broek Kees Jalink Nicolai Sidenius Anastassis Perrakis Wouter H Moolenaar |
| author_facet | Michiel van Veen Elisa Matas-Rico Koen van de Wetering Daniela Leyton-Puig Katarzyna M Kedziora Valentina De Lorenzi Yvette Stijf-Bultsma Bram van den Broek Kees Jalink Nicolai Sidenius Anastassis Perrakis Wouter H Moolenaar |
| author_sort | Michiel van Veen |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-14T07:55:33Z |
| format | Article |
| id | doaj.art-5070f645e7704c60bab1e06d4b70fcf1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-14T07:55:33Z |
| publishDate | 2017-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5070f645e7704c60bab1e06d4b70fcf12022-12-22T02:05:03ZengeLife Sciences Publications LtdeLife2050-084X2017-08-01610.7554/eLife.23649Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cellsMichiel van Veen0Elisa Matas-Rico1Koen van de Wetering2Daniela Leyton-Puig3Katarzyna M Kedziora4Valentina De Lorenzi5Yvette Stijf-Bultsma6Bram van den Broek7Kees Jalink8Nicolai Sidenius9Anastassis Perrakis10https://orcid.org/0000-0002-1151-6227Wouter H Moolenaar11https://orcid.org/0000-0001-7545-198XDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsIFOM, The FIRC Institute of Molecular Oncology, Milan, ItalyDivision of Biochemistry, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsIFOM, The FIRC Institute of Molecular Oncology, Milan, ItalyDivision of Biochemistry, The Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, NetherlandsThe 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.https://elifesciences.org/articles/23649GDE3glycerophosphodiester phosphodiesteraseglycosylphosphatidylinositolsignal transduction |
| spellingShingle | Michiel van Veen Elisa Matas-Rico Koen van de Wetering Daniela Leyton-Puig Katarzyna M Kedziora Valentina De Lorenzi Yvette Stijf-Bultsma Bram van den Broek Kees Jalink Nicolai Sidenius Anastassis Perrakis Wouter H Moolenaar Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells eLife GDE3 glycerophosphodiester phosphodiesterase glycosylphosphatidylinositol signal transduction |
| 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 | GDE3 glycerophosphodiester phosphodiesterase glycosylphosphatidylinositol signal transduction |
| url | https://elifesciences.org/articles/23649 |
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