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New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms
The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761155/ https://www.ncbi.nlm.nih.gov/pubmed/33255171 http://dx.doi.org/10.3390/cells9122531 |
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author | Gorrasi, Anna Petrone, Anna Maria Li Santi, Anna Alfieri, Mariaevelina Montuori, Nunzia Ragno, Pia |
author_facet | Gorrasi, Anna Petrone, Anna Maria Li Santi, Anna Alfieri, Mariaevelina Montuori, Nunzia Ragno, Pia |
author_sort | Gorrasi, Anna |
collection | PubMed |
description | The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, β1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs β1 integrin partitioning to lipid rafts, whereas blocking its association with β1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting β1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs. |
format | Online Article Text |
id | pubmed-7761155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77611552020-12-26 New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms Gorrasi, Anna Petrone, Anna Maria Li Santi, Anna Alfieri, Mariaevelina Montuori, Nunzia Ragno, Pia Cells Article The urokinase (uPA) receptor (uPAR) plays a key role in cell migration. We previously showed that uPAR-negative HEK-293 cells efficiently migrate toward serum but, after uPAR ectopic expression, migrate only in a uPAR-dependent manner. In fact, migration of uPAR-transfected HEK-293 (uPAR-293) cells is impaired by anti-uPAR antibodies, without recovery of the uPAR-independent migration mechanisms formerly active. Prostate carcinoma PC3 cells, which express high endogenous uPAR levels, migrated only through a uPAR-dependent mechanism; in fact, the silencing of uPAR expression inhibited their migration. We hypothesize a crucial role of the uPAR glycosyl-phosphatidyl-inositol (GPI) tail, which promotes uPAR partitioning to lipid rafts, in uPAR-controlled cell migration. Here, we show that removal of the uPAR GPI-tail, or lipid rafts disruption by methyl-beta-cyclodextrin impairs migration of PC3 cells, incapable of uPAR-independent migration, whereas it restores uPAR-independent migration in uPAR-293 cells. We then show that, in PC3 cells, both uPAR signaling partners, β1 integrins and receptors for formylated peptides (FPRs), partly associate with lipid rafts. Inhibition of their interaction with uPAR impairs this association and impairs cell migration. Interestingly, blocking uPAR association with FPRs also impairs β1 integrin partitioning to lipid rafts, whereas blocking its association with β1 integrins has no effect on FPRs partitioning. On these bases, we propose that uPAR controls cell migration by connecting β1 integrins and FPRs and, through its GPI tail, by driving them into lipid rafts, thus promoting pro-migratory signals. uPAR-mediated partitioning of integrins to lipid rafts is strictly dependent on uPAR association with FPRs. MDPI 2020-11-24 /pmc/articles/PMC7761155/ /pubmed/33255171 http://dx.doi.org/10.3390/cells9122531 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gorrasi, Anna Petrone, Anna Maria Li Santi, Anna Alfieri, Mariaevelina Montuori, Nunzia Ragno, Pia New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title | New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title_full | New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title_fullStr | New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title_full_unstemmed | New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title_short | New Pieces in the Puzzle of uPAR Role in Cell Migration Mechanisms |
title_sort | new pieces in the puzzle of upar role in cell migration mechanisms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761155/ https://www.ncbi.nlm.nih.gov/pubmed/33255171 http://dx.doi.org/10.3390/cells9122531 |
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