A Role for the Mitogen-activated Protein Kinase Kinase Kinase 1 in Epithelial Wound Healing

Abstract

The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1) mediates activin B 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 NH 2 -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.

Role of mitogen-activated protein kinase kinase kinases in signal integration

“…MEKK3 knockout is embryo lethal, displaying inadequate fetal-maternal vascularization (Yang et al, 2000), whereas loss of MEKK4 activity is largely perinatal lethal, and is associated with defective neural tube closure . In contrast, both MEKK1 and MEKK2 are developmentally dispensable, with recent evidence suggesting that losses of these proteins are associated with impaired tissue remodeling associated with wound healing and homeostasis Yamashita et al, 2005;Deng et al, 2006). These models indicate that, while other MKKKs also regulate activation of these MAPK modules, the MEKKs each control one or more cellular functions that are not redundant and thus not compensated for by other MKKKs.…”

Differential transmission of MEKK1 morphogenetic signals by JNK1 and JNK2

“…Adenoviruses containing cDNA for an N-terminal hemagglutin (HA)-tagged human MEKK1 [MEKK1(WT)] or for HA-MEKK1(KM), a ATPbinding site mutant, were described elsewhere (Deng et al, 2006). The plasmids for Exp-MEKK1, HA-JNK1 and HA-JNK2 were described previously (Xia et al, 1998) and the plasmids for HA-JNK1(CTN) and HA-JNK2 (GTS) containing site-specific mutations at amino acids 177 and 179 sites were generated using a QuikChange site-directed mutagenesis kit (Stratagene).…”

Defective eyelid leading edge cell migration in C57BL/6-corneal opacity mice with an “eye open at birth” phenotype

“…Therefore, the epithelium in eyelids moved very slowly. There was no significant difference in cell migration ability, as determined using a wound-healing assay, between adult wild-type and MEKK1 -/-mice exhibiting the EOB phenotype (Deng et al, 2006). It is likely that abundant subcutaneous cytokines may serve as an alternative pathway to promote wound healing.…”

“…The developing eyelids are composed of loose mesenchyme covered by an epithelial sheet, the epidermis (outer surface), and conjunctiva (inner surface), as well as the periderm, which covers the epidermis (Deng et al, 2006). Only the peridermal and epidermal layers are involved in eyelid fusion.…”