Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins
- 1 July 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 297 (1), L97-L108
- https://doi.org/10.1152/ajplung.90283.2008
Abstract
Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize αvβ5to attach to vitronectin, predominantly α5β1(and αvβ3) to attach to fibronectin, and α1β1, α2β1, and α3β1to attach to collagen. Blocking studies with α-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple α-integrins but with a preference for α3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung.Keywords
This publication has 71 references indexed in Scilit:
- Focal Adhesion Kinase (FAK)-related Non-kinase Inhibits Myofibroblast Differentiation through Differential MAPK Activation in a FAK-dependent MannerJournal of Biological Chemistry, 2008
- Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosisThe Journal of Experimental Medicine, 2008
- Inhibition of Integrin αvβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung FibrosisAmerican Journal of Respiratory and Critical Care Medicine, 2008
- Plasminogen Activation–Induced Pericellular Fibronectin Proteolysis Promotes Fibroblast ApoptosisAmerican Journal of Respiratory Cell and Molecular Biology, 2008
- Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast DifferentiationMolecular Biology of the Cell, 2007
- uPAR-induced cell adhesion and migration: vitronectin provides the keyThe Journal of cell biology, 2007
- Urokinase Receptors Are Required for α5β1 Integrin-mediated Signaling in Tumor CellsJournal of Biological Chemistry, 2007
- Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrixProceedings of the National Academy of Sciences of the United States of America, 2006
- Regulation of α5β1 integrin conformation and function by urokinase receptor bindingThe Journal of cell biology, 2005
- Inhibition of Angiogenesis in Vivo by Plasminogen Activator Inhibitor-1Journal of Biological Chemistry, 2001