The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor.
The receptor (CXCR4) for the stromal-derived factor-1 (SDF1) and the urokinase-receptor (uPAR) are up-regulated in various tumors. We show that CXCR4-transfected cells migrate toward SDF1 on collagen (CG) and do not on vitronectin (VN). Co-expression of cell-surface uPAR, which is a VN receptor, impairs SDF1-induced migration on CG and allows migration on VN. Blocking fMLP receptors (fMLP-R), alpha-v integrins or the uPAR region capable to interact with fMLP-Rs, impairs migration of uPAR/CXCR4-transfected cells on VN and restores their migration on CG. uPAR co-expression also reduces the adherence of CXCR4-expressing cells to various components of the extracellular matrix (ECM) and influences the partitioning of beta1 and alpha-v integrins to membrane lipid-rafts, affecting ECM-dependent signaling. uPAR interference in CXCR4 activity has been confirmed in cells from prostate carcinoma. Our results demonstrate that uPAR expression regulates the adhesive and migratory ability of CXCR4-expressing cells through a mechanism involving fMLP receptors and alpha-v integrins.
Montuori
Nunzia
N
Department of Cellular and Molecular Biology and Pathology, Federico II University, Naples, Italy.
Bifulco
Katia
K
Carriero
Maria Vincenza
MV
La Penna
Claudio
C
Visconte
Valeria
V
Alfano
Daniela
D
Pesapane
Ada
A
Rossi
Francesca Wanda
FW
Salzano
Salvatore
S
Rossi
Guido
G
Ragno
Pia
P
D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D018613:Microscopy, Confocal; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034622:RNA Interference; D020239:Receptor Cross-Talk; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019096:Vitronectin / Q000378:metabolism
D054377:Chemokine CXCL12; C469985:FPR3 protein, human; D039081:Integrin alpha5beta1; D019718:Receptors, CXCR4; D044042:Receptors, Formyl Peptide; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin; D003094:Collagen; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3