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Remodeling of the extracellular matrix during tissue development, wound repair and tumor cell invasion depends on the coordinated regulation of cell adhesion receptors, matrix proteins and enzymes that proteolyse the extracellular matrix. Integrin alpha3beta1 is a major receptor on epidermal keratinocytes for laminin-5 in the cutaneous basement membrane and is required for normal basement membrane organization during skin development. alpha3beta1 is also expressed at high levels in the majority of adherent transformed cells and in most tumors, and it could have similar roles in extracellular matrix remodeling during tumorigenesis and cell invasion. In the present study, we show that alpha3beta1 expression is required in immortalized mouse keratinocytes (MK) for the production of the matrix metalloproteinase MMP-9/gelatinase B, an MMP that is coexpressed with alpha3beta1 in epithelial cell carcinomas and during wound healing, and contributes to the invasive potential of some tumor cells. MMP-9 was expressed in MK cells derived from wild-type mice, but not in MK cells derived from alpha3-null mice. Reconstitution of alpha3beta1 expression in alpha3-null MK cells through transfection with the alpha3 subunit restored MMP-9 secretion, indicating an alpha3beta1-dependent pathway for MMP-9 production. alpha3beta1-dependent expression of MMP-9 was associated with the immortalized phenotype, since nonimmortalized, primary keratinocytes required soluble growth factors, but not alpha3beta1, for efficient expression of MMP-9. Our results suggest that an alpha3beta1-independent pathway(s) for MMP-9 production is suppressed in keratinocytes immortalized with large T antigen, and that an alpha3beta1-dependent pathway is required for sustained production of MMP-9 in the absence of other pathways.