Integrin α3β1 potentiates TGFβ-mediated induction of MMP-9 in immortalized keratinocytes

Transforming growth factor-beta (TGF beta) signaling pathways regulate a number of keratinocyte functions during epidermal carcinogenesis and wound healing, including proliferation, survival, and migration. TGF beta can induce expression of the matrix metalloproteinase-9 (MMP-9), which has critical roles in promoting extracellular matrix remodeling and angiogenesis during tumorigenesis and tissue repair. Integrin alpha 3 beta 1 is a cell adhesion receptor for laminin-332/laminin-5 with important roles in the survival and motility of epidermal keratinocytes. We previously reported that alpha 3 beta 1 induces the expression of MMP-9 in immortalized keratinocytes. In this study, we show that enclogenous TGF beta is required for maximal MMP-9 expression, and that alpha 3 beta 1 is required for full induction of MMP-9 protein and mRNA in response to TGF beta. This, regulation was not observed in nonimmortalized, primary keratinocytes, indicating that coordinate regulation of MMP-9 by 0,61 and TGF beta is a property of immortalized cells. alpha 3 beta 1 did not regulate enclogenous TGF beta gene expression, TGF beta bioavailability, or TGF beta-Smad signaling. However, the combined inductive effects of TGF beta and alpha 3 beta 1 on MMP-9 were suppressed by a Src family kinase (SFK) inhibitor, indicating involvement of a SFK pathway. These findings provide early evidence of a role for alpha 3 beta 1 in augmenting TGF beta-mediated induction of MMP-9 in immortalized or transformed keratinocytes during skin carcinogenesis.