Urinary-type plasminogen activator (uPA) expression and uPA receptor localization are regulated by alpha(3)beta(1) integrin in oral keratinocytes

Expression of urinary-type plasminogen activator (uPA) and its receptor (uP AR) is correlated with matrix proteolysis, cell adhesion, motility, and inv asion. To evaluate the functional link between adhesion and proteolysis in gingival keratinocytes (pp126), cells were treated with immobilized integri n antibodies to induce integrin clustering Clustering of alpha(3) and beta( 1) integrin subunits, but not alpha(2), alpha(5), alpha(6), or beta(4), enh anced uPA secretion. Bead-immobilized laminin-5 and collagen I, two major a lpha(3)beta(1) 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. alpha(3)beta(1) integrin c lustering induced extracellular signal-regulated kinase 1/2 phosphorylation , and both uPA induction and extracellular signal-regulated kinase activati on were blocked by the mitogen-activated protein kinase/extracellular signa l-regulated kinase kinase inhibitor PD98059, Integrin aggregation also prom oted a dramatic redistribution of uPAR on the cell surface to sites of clus tered alpha(3)beta(1) integrins. Co-immunoprecipitation of beta(1) integrin with uPAR provided further evidence that protein-protein interactions betw een uPAR and beta(1) integrin control uPAR distribution, As a functional co nsequence of uPA up-regulation and uPA-mediated plasminogen activation, the globular domain of the laminin-5 alpha(3) subunit, a major pp126 matrix pr otein, was proteolytically processed from a 190-kDa form to a 160-kDa speci es, Laminin-5 containing the 160-kDa alpha(3) subunit efficiently nucleates hemidesmosome formation and reduces cell motility, Together, these data su ggest that multivalent aggregation of the alpha(3)beta(1) integrin regulate s proteinase expression, matrix proteolysis, and subsequent cellular behavi or.