Reepithelialization during cutaneous wound healing involves numerous signals that result in basal keratinocyte activation, spreading, and migration, all linked to a loosening of cell-cell adhesion structures. The transcription factor Slug is required for this process, and EGF treatment of human keratinocytes induced activating phosphorylation of Erk5 that coincides with slug transcription. Accordingly, ectopic activation of Erk5 led to increased Slug mRNA levels and faster wound healing, whereas keratinocyte migration was totally blocked by Erk5 pathway inhibition. Expression of a shRNA specific for Erk5 strongly diminished Erk5 levels in keratinocytes and significantly decreased their motility response to EGF, along with induction of Slug expression. These Erk5-deprived keratinocytes showed an altered, more compact morphology, along with disruption of desmosome organization. Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF.
Erk5 controls Slug expression and keratinocyte activation during wound healing
Arnoux, V.; Nassour, M.; L'Helgoualc'h, A.; Hipskind, R. A.; Savagner, P.
Mol Biol Cell
2008-11 / vol 19 / pages 4738-49
E07-10-1078 [pii] 10.1091/mbc.E07-10-1078
1939-4586 (Electronic) 1059-1524 (Linking)
Humans; Animals; Mice; Promoter Regions, Genetic; RNA, Small Interfering/metabolism; Cricetinae; Phosphorylation/drug effects; Mitogen-Activated Protein Kinase 7/*metabolism; Gene Expression Regulation/drug effects; CHO Cells; Cricetulus; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Cell Adhesion/drug effects; Epidermal Growth Factor/pharmacology; *Wound Healing/drug effects; Cytoskeleton/drug effects/metabolism; Epithelium/drug effects/metabolism; Keratinocytes/*cytology/drug effects/*enzymology; Receptor, Epidermal Growth Factor/metabolism; Transcription Factors/deficiency/*genetics/metabolism