Urokinase-type Plasminogen Activator Receptor (uPAR) Ligation Induces a Raft-localized Integrin Signaling Switch That Mediates the Hypermotile Phenotype of Fibrotic Fibroblasts

摘要: 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 lung fibroblasts from patients idiopathic pulmonary fibrosis (IPF) exhibit hypermotile phenotype. This study was undertaken elucidate the molecular mechanism whereby uPAR ligation its cognate ligand, urokinase, induces motile phenotype in human fibroblasts. We found urokinase binding (amino-terminal fragment) leads enhanced migration of on fibronectin protease-independent, raft-dependent manner. Ligation amino-terminal fragment recruited α5β1 integrin acylated form Src family kinase, Fyn, rafts. biological consequences this translocation were an increase fibroblast motility switch integrin-initiated signal pathway for away raft-independent focal adhesion kinase toward caveolin-Fyn-Shc pathway. Furthermore, homologous peptide as well antibody competes β1 ability block effect. In addition, relative insensitivity cholesterol depletion suggests interactions drive integrin-acylated Fyn signaling complexes into rafts upon through protein-protein interactions. novel leading IPF patient-derived fibroblasts, seen ligation. dependent, fibrotic matrix-selective, profibrotic may be amenable targeted therapeutics designed ameliorate IPF.