Cdc42 Inhibits ERK-mediated Collagenase-1 (MMP-1) Expression in Collagen-Activated Human Keratinocytes

Following injury, keratinocytes switch gene expression programs from one that promotes differentiation to one that supports migration. A common feature of human wounds and ulcerations of any form is the expression of MMP-1 (collagenase-1) by leading-edge basal keratinocytes migrating across the dermal or provisional matrix. Induction of MMP-1 occurs by signaling from the α(2)β(1) integrin in contact with dermal fibrillar type I collagen, and the activity of MMP-1 is required for human keratinocytes to migrate on collagen. Thus, MMP-1 serves a critical role in repair of damaged human skin. Here, we evaluated the mechanisms controlling MMP-1 expression in primary human keratinocytes from neonatal foreskin and adult female skin. Our results demonstrate that shortly following contact with type I collagen, ERK and p38 MAPK were markedly activated, whereas JNK phosphorylation remained at basal levels. ERK inhibition dramatically blocked collagen-stimulated MMP-1 expression in keratinocytes. In contrast, inhibiting p38 or JNK pathways had no effect on MMP-1 production. Moreover, investigating the role of Rho GTPases revealed that Cdc42 attenuates MMP-1 expression by suppressing ERK activity. Thus, our data indicates that injured keratinocytes induce MMP-1 expression through ERK activation, and this process is negatively regulated by Cdc42 activity.