Src-dependence and pertussis-toxin sensitivity of urokinase receptor-dependent chemotaxis and cytoskeleton reorganization in rat smooth muscle cells

The catalytically inactive precursor of urokinase-type plasminogen activator (pro-u-PA) induced a chemotactic response in rat smooth muscle cells (RSMC) through binding to the membrane receptor of urokinase (u-PA receptor [u-PAR]). A soluble form of u-PAR activated by chymotrypsin cleavage as well a...

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Bibliographic Details
Published in:Blood 1999-07, Vol.94 (2), p.649-662
Main Authors: DEGRYSE, B, RESNATI, M, RABBANI, S. A, VILLA, A, FAZIOLI, F, BLASI, F
Format: Article
Language:English
Subjects:
Actins - analysis
Animals
Biological and medical sciences
Blood coagulation. Blood cells
Cell Size - drug effects
Cells, Cultured
Chemotaxis - drug effects
Cytoskeleton - drug effects
Cytoskeleton - ultrastructure
Enzyme Precursors - pharmacology
Fundamental and applied biological sciences. Psychology
General aspects, investigation methods, hemostasis, fibrinolysis
GTP-Binding Proteins - metabolism
Mice
Microscopy, Fluorescence
Molecular and cellular biology
Muscle, Smooth - cytology
Muscle, Smooth - drug effects
Muscle, Smooth - ultrastructure
Peptide Fragments - pharmacology
Pertussis Toxin
Protein Conformation
Proto-Oncogene Proteins pp60(c-src) - physiology
Rats
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - physiology
Receptors, Urokinase Plasminogen Activator
Receptors, Vitronectin - metabolism
Recombinant Proteins - pharmacology
Signal Transduction - drug effects
src-Family Kinases - physiology
Urokinase-Type Plasminogen Activator - pharmacology
Virulence Factors, Bordetella - pharmacology
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Summary:The catalytically inactive precursor of urokinase-type plasminogen activator (pro-u-PA) induced a chemotactic response in rat smooth muscle cells (RSMC) through binding to the membrane receptor of urokinase (u-PA receptor [u-PAR]). A soluble form of u-PAR activated by chymotrypsin cleavage as well as a peptide located between domain 1 and 2 of u-PAR reproduced the effect of pro-u-PA on cell migration. The chemotactic pro-u-PA effect correlates with a dramatic reorganization of actin cytoskeleton, of adhesion plaques, and with major cell shape changes in RSMC. Pro-u-PA induced a decrease in stress fiber content, membrane ruffling, actin ring formation, and disruption leading to the characteristic elongated cell shape of motile cells with an actin semi-ring located close to the leading edge of cells. u-PAR effects on both chemotaxis and cytoskeleton were sensitive to pertussis toxin and, hence, possibly require G proteins. u-PAR effects are accompanied by a relocation of u-PAR, vitronectin receptor (VNR) alphavbeta3, beta1 integrin subunit, and Src tyrosine kinase to the leading membrane of migrating cells. In conclusion, our data show that pro-u-PA, via binding to u-PAR, controls a signaling pathway, regulated by tyrosine kinases and possibly G proteins, leading to cell cytoskeleton reorganization and cell migration.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.v94.2.649