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) 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 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.
Deng
Maoxian
M
Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA.
Chen
Wei-Li
WL
Takatori
Atsushi
A
Peng
Zhimin
Z
Zhang
Lin
L
Mongan
Maureen
M
Parthasarathy
Ranjani
R
Sartor
Maureen
M
Miller
Marian
M
Yang
Jianhua
J
Su
Bing
B
Kao
Winston W-Y
WW
Xia
Ying
Y
D028341:Activins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement; D003315:Cornea / Q000166:cytology; D004789:Enzyme Activation; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000201:enzymology* / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000166:cytology / Q000473:pathology; D014945:Wound Healing / Q000276:immunology*
C044147:activin B; D028341:Activins; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human