ArticleThe Journal of biological chemistry2014
Urokinase-type plasminogen activator receptor (uPAR) ligation induces a raft-localized integrin signaling switch that mediates the hypermotile phenotype of fibrotic fibroblasts.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Hydrolysis and depletion of phosphatidylglycerol at peak murine acute lung injury.Journal of lipid research · 2026Article
- uPAR deficiency triggers TGFβ1-mediated fibrotic remodeling in a cardiac perivascular-like microenvironment.Stem cell research & therapy · 2026Article
- Metabolites beyond metabolism: Exploring their atypical roles in protein modification and signaling transduction.Chinese medical journal · 2026Review
- Integrins and pulmonary fibrosis: Pathogenic roles and therapeutic opportunities.Biomolecules & biomedicine · 2025Review
- Overexpression of Plg-RAdipocyte · 2023Article
- The plasminogen receptor Plg-RJournal of thrombosis and haemostasis : JTH · 2022Article
- Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View.Frontiers in cell and developmental biology · 2022Review
- Isolation of Lipid Rafts by the Detergent-Based and Non-detergent-Based Methods for Localization of GPCRs with Immunoblotting and Laser Scanning Confocal Microscopy.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Article
- Molecular imaging of the urokinase plasminogen activator receptor: opportunities beyond cancer.EJNMMI research · 2020Review
- Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation.Science signaling · 2019Article
- Extracellular matrix in lung development, homeostasis and disease.Matrix biology : journal of the International Society for Matrix Biology · 2018Review
- Integration of Genome-Wide DNA Methylation and Transcription Uncovered Aberrant Methylation-Regulated Genes and Pathways in the Peripheral Blood Mononuclear Cells of Systemic Sclerosis.International journal of rheumatology · 2018Article
- A Cross Talk between Neuronal Urokinase-type Plasminogen Activator (uPA) and Astrocytic uPA Receptor (uPAR) Promotes Astrocytic Activation and Synaptic Recovery in the Ischemic Brain.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.Genome medicine · 2017Article
- The Microtubule Inhibitor Podofilox Inhibits an Early Entry Step of Human Cytomegalovirus.Viruses · 2016Article
- Effect of urokinase-type plasminogen activator system in gastric cancer with peritoneal metastasis.Oncology letters · 2016Article
- Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype.The Journal of biological chemistry · 2016Article
- TRPV4 Mechanosensitive Ion Channel Regulates Lipopolysaccharide-Stimulated Macrophage Phagocytosis.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- Effect and prognostic significance of the KAI1 gene in human gastric carcinoma.Oncology letters · 2015Article
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13 authors.
Funding
Abstract
The urokinase-type plasminogen activator receptor (uPAR) is a glycosylphosphatidylinositol-linked membrane protein with no cytosolic domain that localizes to lipid raft microdomains. Our laboratory and others have documented that lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibit a hypermotile phenotype. This study was undertaken to elucidate the molecular mechanism whereby uPAR ligation with its cognate ligand, urokinase, induces a motile phenotype in human lung fibroblasts. We found that uPAR ligation with the urokinase receptor binding domain (amino-terminal fragment) leads to enhanced migration of fibroblasts on fibronectin in a protease-independent, lipid raft-dependent manner. Ligation of uPAR with the amino-terminal fragment recruited α5β1 integrin and the acylated form of the Src family kinase, Fyn, to lipid rafts. The biological consequences of this translocation were an increase in fibroblast motility and a switch of the integrin-initiated signal pathway for migration away from the lipid raft-independent focal adhesion kinase pathway and toward a lipid raft-dependent caveolin-Fyn-Shc pathway. Furthermore, an integrin homologous peptide as well as an antibody that competes with β1 for uPAR binding have the ability to block this effect. In addition, its relative insensitivity to cholesterol depletion suggests that the interactions of α5β1 integrin and uPAR drive the translocation of α5β1 integrin-acylated Fyn signaling complexes into lipid rafts upon uPAR ligation through protein-protein interactions. This signal switch is a novel pathway leading to the hypermotile phenotype of IPF patient-derived fibroblasts, seen with uPAR ligation. This uPAR dependent, fibrotic matrix-selective, and profibrotic fibroblast phenotype may be amenable to targeted therapeutics designed to ameliorate IPF.
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