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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...

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Autores principales: Gorrasi, Anna, Petrone, Anna Maria, Li Santi, Anna, Alfieri, Mariaevelina, Montuori, Nunzia, Ragno, Pia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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.
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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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