In this study we analyzed the proteolytic activity of MMP-19 and its impact on keratinocyte migration. In the HaCaT keratinocyte cell line overexpressing wild-type MMP-19 (HaCaT-WT), transmigration through fibrin and type IV collagen matrices was significantly increased compared to cells harboring a catalytically inactive mutant (HaCaT-EA). Studying the expression of MMP-19 in early stages of squamous cell cancer (SCC), we found co-localization of MMP-19 and laminin 5 at the invading tumor front but not in suprabasal epidermis of the tumor. Examination of laminin 5 processing revealed increased processing of the γ2 chain in the medium and matrix of HaCaT-WT cells and degradation by recombinant human MMP-19 to 105-kDa and 80-kDa fragments. Parental HaCaT grown on the matrix of HaCaT-WT and HaCaT-EA cells displayed differential tyrosine phosphorylation. Using integrin blocking and stimulating antibodies we could attribute these differences to a shift from β4-integrin-dependent signaling on the HaCaT-EA matrix toward α3-integrin-dependent signaling on the HaCaT-WT matrix. As a consequence, parental HaCaT showed increased migration on the matrix of HaCaT-WT cells. These data suggest that the MMP-19-dependent processing of the γ2 chains leads to the integrin switch favoring epithelial migration and that MMP-19 actively participates in the early stages of SCC invasion.