Erk5 controls Slug expression and keratinocyte activation during wound healing.
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.
Arnoux
Valerie
V
INSERM EMI 229, Genotypes et phenotypes tumoraux, Centre de Recherche en Cancerologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, France.
Nassour
Mayssaa
M
L'Helgoualc'h
Annie
A
Hipskind
Robert A
RA
Savagner
Pierre
P
D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7