The Urokinase Receptor Takes Control of Cell Migration by Recruiting Integrins and FPR1 on the Cell Surface

被引:25
作者
Gorrasi, Anna [1 ]
Santi, Anna Li [1 ]
Amodio, Giuseppina [2 ]
Alfano, Daniela [1 ]
Remondelli, Paolo [2 ]
Montuori, Nunzia [3 ]
Ragno, Pia [1 ]
机构
[1] Univ Salerno, Dept Biol & Chem, I-84100 Salerno, Italy
[2] Univ Salerno, Dept Med & Surg, I-84100 Salerno, Italy
[3] Univ Naples Federico II, Dept Translat Med Sci, Naples, Italy
关键词
PLASMINOGEN-ACTIVATOR RECEPTOR; FORMYL-PEPTIDE RECEPTORS; GROWTH-FACTOR RECEPTORS; MONOCYTE CHEMOTAXIS; UPAR; ADHESION; MOLECULES; CLEAVAGE; BIOLOGY; LIGAND;
D O I
10.1371/journal.pone.0086352
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The receptor (uPAR) of the urokinase-type plasminogen activator (uPA) is crucial in cell migration since it concentrates uPA proteolytic activity at the cell surface, binds vitronectin and associates to integrins. uPAR cross-talk with receptors for the formylated peptide fMLF (fMLF-Rs) has been reported; however, cell-surface uPAR association to fMLF-Rs on the cell membrane has never been explored in detail. We now show that uPAR co-localizes at the cell-surface and co-immunoprecipitates with the high-affinity fMLF-R, FPR1, in uPAR-transfected HEK-293 (uPAR-293) cells. uPAR/beta 1 integrin and FPR1/beta 1 integrin co-localization was also observed. Serum or the WKYMVm peptide (W Pep), a FPR1 ligand, strongly increased all observed co-localizations in uPAR-293 cells, including FPR1/beta 1 integrin co-localization. By contrast, a low FPR1/beta 1 integrin co-localization was observed in uPAR-negative vector-transfected HEK-293 (V-293) cells, that was not increased by serum or W Pep stimulations. The role of uPAR interactions in cell migration was then explored. Both uPAR-293 and V293 control cells efficiently migrated toward serum or purified EGF. However, cell treatments impairing uPAR interactions with fMLF-Rs or integrins, or inhibiting specific cell-signaling mediators abrogated uPAR-293 cell migration, without exerting any effect on V-293 control cells. Accordingly, uPAR depletion by a uPAR-targeting siRNA or uPAR blocking with an anti-uPAR polyclonal antibody in cells constitutively expressing high uPAR levels totally impaired their migration toward serum. Altogether, these results suggest that both uPAR-positive and uPAR-negative cells are able to migrate toward serum; however, uPAR expression renders cell migration totally and irreversibly uPAR-dependent, since it is completely inhibited by uPAR blocking. We propose that uPAR takes control of cell migration by recruiting fMLF-Rs and beta 1 integrins, thus promoting their co-localization at the cell-surface and driving pro-migratory signaling pathways.
引用
收藏
页数:13
相关论文
共 40 条
[1]   RhoB regulates uPAR signalling [J].
Alfano, Daniela ;
Ragno, Pia ;
Stoppelli, M. Patrizia ;
Ridley, Anne J. .
JOURNAL OF CELL SCIENCE, 2012, 125 (10) :2369-2380
[2]   Single Amino Acid Substitutions in the Chemotactic Sequence of Urokinase Receptor Modulate Cell Migration and Invasion [J].
Bifulco, Katia ;
Longanesi-Cattani, Immacolata ;
Franco, Paola ;
Pavone, Vincenzo ;
Mugione, Pietro ;
Di Carluccio, Gioconda ;
Masucci, Maria Teresa ;
Arra, Claudio ;
Pirozzi, Giuseppe ;
Stoppelli, Maria Patrizia ;
Carriero, Maria Vincenza .
PLOS ONE, 2012, 7 (09)
[3]   UROKINASE PLASMINOGEN-ACTIVATOR RECEPTOR, BETA-2-INTEGRINS, AND SRC-KINASES WITHIN A SINGLE RECEPTOR COMPLEX OF HUMAN MONOCYTES [J].
BOHUSLAV, J ;
HOREJSI, V ;
HANSMANN, C ;
STOCKL, J ;
WEIDLE, UH ;
MAJDIC, O ;
BARTKE, I ;
KNAPP, W ;
STOCKINGER, H .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (04) :1381-1390
[4]   Monomer-dimer dynamics and distribution of GPI-anchored uPAR are determined by cell surface protein assemblies [J].
Caiolfa, Valeria R. ;
Zamai, Moreno ;
Malengo, Gabriele ;
Andolfo, Annapaola ;
Madsen, Chris D. ;
Sutin, Jason ;
Digman, Michelle A. ;
Gratton, Enrico ;
Blasi, Francesco ;
Sidenius, Nicolai .
JOURNAL OF CELL BIOLOGY, 2007, 179 (05) :1067-1082
[5]   Biology of chemokine and classical chemoattractant receptors: Differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells [J].
Campbell, JJ ;
Qin, SX ;
Bacon, KB ;
Mackay, CR ;
Butcher, EC .
JOURNAL OF CELL BIOLOGY, 1996, 134 (01) :255-266
[6]   A region in urokinase plasminogen receptor domain III controlling a functional association with α5β1 integrin and tumor growth [J].
Chaurasia, Pratima ;
Aguirre-Ghiso, Julio A. ;
Liang, Olin D. ;
Gardsvoll, Henrik ;
Ploug, Michael ;
Ossowski, Liliana .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (21) :14852-14863
[7]   Interactions between growth factor receptors and adhesion molecules: breaking the rules [J].
Comoglio, PM ;
Boccaccio, C ;
Trusolino, L .
CURRENT OPINION IN CELL BIOLOGY, 2003, 15 (05) :565-571
[8]   Dimerization controls the lipid raft partitioning of uPAR/CD87 and regulates its biological functions [J].
Cunningham, O ;
Andolfo, A ;
Santovito, ML ;
Iuzzolino, L ;
Blasi, F ;
Sidenius, N .
EMBO JOURNAL, 2003, 22 (22) :5994-6003
[9]   Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity - Generation of a new integrin inhibitor [J].
Degryse, B ;
Resnati, M ;
Czekay, RP ;
Loskutoff, DJ ;
Blasi, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (26) :24792-24803
[10]   The Urokinase Receptor Interactome [J].
Eden, Gabriele ;
Archinti, Marco ;
Furlan, Federico ;
Murphy, Ronan ;
Degryse, Bernard .
CURRENT PHARMACEUTICAL DESIGN, 2011, 17 (19) :1874-1889