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Originally published as MBC in Press, 10.1091/mbc.E07-10-1078 on August 20, 2008

Vol. 19, Issue 11, 4738-4749, November 2008

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Erk5 Controls Slug Expression and Keratinocyte Activation during Wound Healing

Valerie Arnoux*, Mayssaa Nassour*, Annie L'Helgoualc'h{dagger}, Robert A. Hipskind{ddagger}, and Pierre Savagner*

*INSERM EMI 229, Genotypes et phenotypes tumoraux, Centre de Recherche en Cancerologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, France; {ddagger}Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, 34293 Montpellier, France; and {dagger}INSERM U456, 35043 Rennes, France

Submitted October 26, 2007; Revised August 8, 2008; Accepted August 12, 2008
Monitoring Editor: M. Bishr Omary

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.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-10-1078) on August 20, 2008.

Address correspondence to: Pierre Savagner (psavagner{at}valdorel.fnclcc.fr)






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