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Vol. 17, Issue 8, 3446-3455, August 2006

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

Maoxian Deng^*,, Wei-Li Chen^,,, Atsushi Takatori^*, Zhimin Peng^*, Lin Zhang^*,||, Maureen Mongan^*, Ranjani Parthasarathy^*, Maureen Sartor^*, Marian Miller^*, Jianhua Yang^¶, Bing Su^¶, Winston W.-Y. Kao, and Ying Xia^*,

*Departments of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056; Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China; Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, OH 45267; ^||Department of Central Lab, Southern Medical University, Tonghe, Guangzhou, People's Republic of China; and ^¶Department of Immunology, M. D. Anderson Cancer Center, University of Texas, Houston, TX 77030

Submitted February 6, 2006; Revised May 15, 2006; Accepted May 25, 2006
Monitoring Editor: J. Silvio Gutkind

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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

These authors contributed equally to this work.

Address correspondence to: Ying Xia ( xiay{at}email.uc.edu)

Abbreviations used: ECM, extracellular matrix; iRNA, interfering RNA; JNK, Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MEKK, mitogen-activated protein kinase kinase kinase; PAI, plasminogen activator inhibitor

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