A role for the mitogen-activated protein kinase kinase kinase 1 in epithelial wound healing

The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1), also known as MAP3K1, mediates activin B (ActB) signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization. Hybridization was performed using 3 x wild type vs Map3k1 ko control, 3x wild type vs Map3k1 ko ActB, 3x wild type ActB vs Map3k1 ko control and 3x wild type ActB vs Map3k1 ko ActB