Arnoux Valerie, Nassour Mayssaa, L'Helgoualc'h Annie, Hipskind Robert A, Savagner Pierre
INSERM EMI 229, Genotypes et phenotypes tumoraux, Centre de Recherche en Cancerologie de Montpellier, CRLC Val d'Aurelle-Paul Lamarque, 34298 Montpellier, France.
Mol Biol Cell. 2008 Nov;19(11):4738-49. doi: 10.1091/mbc.e07-10-1078. Epub 2008 Aug 20.
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.
皮肤伤口愈合过程中的再上皮化涉及众多信号，这些信号导致基底角质形成细胞活化、铺展和迁移，所有这些都与细胞间粘附结构的松弛有关。转录因子Slug是这一过程所必需的，用表皮生长因子（EGF）处理人角质形成细胞会诱导细胞外调节蛋白激酶5（Erk5）的激活磷酸化，这与Slug转录同时发生。因此，Erk5的异位激活导致Slug mRNA水平升高和伤口愈合加快，而角质形成细胞迁移则被Erk5途径抑制完全阻断。对Erk5特异的短发夹RNA（shRNA）的表达显著降低了角质形成细胞中Erk5的水平，并显著降低了它们对EGF的运动反应，同时诱导了Slug表达。这些缺乏Erk5的角质形成细胞显示出形态改变，更加紧凑，同时桥粒组织受到破坏。因此，它们形成细胞聚集体的能力也发生了改变。这些结果表明，在用EGF处理的角质形成细胞中，一种新的表皮生长因子受体（EGFR）/Erk5/Slug途径参与了细胞骨架组织和细胞运动的调控。
