Phosphatidylinositol 3-kinase activity in epidermal growth factor-stimulated matrix metalloproteinase-9 production and cell surface association

Activation of the epidermal growth factor (EGF) receptor regulates many pro cesses associated with metastasis. including modulation of cell: cell and c ell:substrate interactions. production of matrix-degrading proteinases, and cellular migration. We have demonstrated previously that EGF stimulates mi gration and matrix metalloproteinase (MMP)-9-dependent invasion of ovarian cancer cells. In this study. we compare the roles of EGF-induced phosphatid ylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) acti vities in regulation of cellular responses associated with ovarian tumor ce ll metastasis. Inhibition of PI3K and MAPK activity impairs EGF-stimulated cell migration, in vitro invasion, and MMP-9 production. PI3K activity is n ot required for growth factor disruption of cell:cell junctions, whereas in hibitors of extracellular signal-regulated kinase (ERK)1/ERK2 activation an d p38 MAPK activity block EGF-dependent junction dissolution. EGF promotes pro-MMP-9 binding to the cell surface through a mechanism that is independe nt of extracellular enzyme concentration. Interestingly, inhibition of PI3K activity abolishes EGF-induced cell surface association of pro-MMP-9, wher eas inhibitors of MAPKs only partially block the response. These data sugge st that EGF receptor activation promotes a PI3K-dependent induction of a ce ll surface pro-MMP-9 binding component that may facilitate gelatinase-media ted cellular invasion and supports an expanded role for elevated PI3K activ ity in cellular responses associated with ovarian tumor metastasis. In addi tion, our findings support the hypothesis that divergent kinase activities regulate distinct cellular events associated with growth factor-induced inv asion of ovarian cancer cells.