Urinary-type Plasminogen Activator (uPA) Expression and uPA Receptor Localization Are Regulated by α3β1Integrin in Oral Keratinocytes

• Published in: The Journal of biological chemistry Vol. 275; no. 31; pp. 23869 - 23876
• Main Authors: Ghosh, Supurna, Brown, Renee, Jones, Jonathan C.R., Ellerbroek, Shawn M., Stack, M. Sharon
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 04.08.2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M000935200

Expression of urinary-type plasminogen activator (uPA) and its receptor (uPAR) is correlated with matrix proteolysis, cell adhesion, motility, and invasion. To evaluate the functional link between adhesion and proteolysis in gingival keratinocytes (pp126), cells were treated with immobilized integrin antibodies to induce integrin clustering. Clustering of α3 and β1 integrin subunits, but not α2, α5, α6, or β4, enhanced uPA secretion. Bead-immobilized laminin-5 and collagen I, two major α3β1 ligands, also induced uPA expression. Coordinate regulation of the serpin plasminogen activator inhibitor 1 was also apparent; however, a net increase in uPA activity was predominant. α3β1 integrin clustering induced extracellular signal-regulated kinase 1/2 phosphorylation, and both uPA induction and extracellular signal-regulated kinase activation were blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059. Integrin aggregation also promoted a dramatic redistribution of uPAR on the cell surface to sites of clustered α3β1 integrins. Co-immunoprecipitation of β1 integrin with uPAR provided further evidence that protein-protein interactions between uPAR and β1 integrin control uPAR distribution. As a functional consequence of uPA up-regulation and uPA-mediated plasminogen activation, the globular domain of the laminin-5 α3subunit, a major pp126 matrix protein, was proteolytically processed from a 190-kDa form to a 160-kDa species. Laminin-5 containing the 160-kDa α3 subunit efficiently nucleates hemidesmosome formation and reduces cell motility. Together, these data suggest that multivalent aggregation of the α3β1integrin regulates proteinase expression, matrix proteolysis, and subsequent cellular behavior.