The expression of hepatocyte growth factor (HGF) receptor, encoded by the Met oncogene, is elevated in ovarian and a variety of cancers. Here we show that human ovarian cancer cells with high Met expression were more sensitive to the cell motility and invasion effect of HGF. Met down-regulation by small interfering RNAs or K252a resulted in reduced migration in response to HGF. The invasive/migratory phenotype activated by HGF can be blocked by specific inhibitors of the phosphatidylinositol-3-kinase (PI3K) cascade, inhibitor of p70S6K, and also the expression of a dominant-negative Akt, demonstrating that HGF transmits the motogenic signal through PI3K and Akt to p70S6K. A significant role for p70S6K in cell invasion is further supported by the observation that expression of constitutively active forms of p70S6K is sufficient to induce invasive and migratory phenotypes in ovarian cancer cells. Importantly, activation of p70S6K stimulated expression and proteolytic activity of matrix metalloproteinase (MMP)-9 and cellular invasion, whereas it had little effect on MMP-2, suggesting for the first time that MMP-9 up-regulation by p70S6K as a key step for HGF-induced invasion and migration. These data suggest that interfering p70S6K may provide a novel means of controlling tumor cell invasiveness.