Atypical protein kinase C isoforms differentially regulate directional keratinocyte migration during wound healing
Atypical protein kinase C isoforms differentially regulate directional keratinocyte migration during wound healing
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DOI：
10.1016/j.jdermsci.2019.01.001
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发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Osada, Shin-Ichi
中科院分区：
文献类型：
--
作者：
Noguchi, Natsuko;Hirose, Tomonori;Osada, Shin-Ichi
背景：表皮具有再生特性，只有在创伤后才变得明显。非典型蛋白激酶C(APKC)亚型aPKC Zeta和aPKC lambda与Par3和Par6形成三元复合体，在建立和维持上皮细胞极性中起关键作用。APKC lambda的表皮缺失导致毛囊干细胞的进行性枯竭。目的：阐明aPKC Zeta和aPKC lambda在皮肤创面愈合中的功能差异。方法：利用两种aPKC亚型基因缺失的突变小鼠，比较体内皮肤创面愈合过程。我们还利用每个突变小鼠建立的原代角质形成细胞，分析了aPKC Zeta和aPKC lambda在体外细胞增殖、定向细胞迁移和微管形成方面的功能差异。结果：表皮特异性aPKC lambda基因敲除小鼠的伤口愈合明显延迟。在PKC lambda缺失的角质形成细胞中，细胞向伤口突出的正确方向因Par6β的不稳定而被破坏。在缺失了lambda的角质形成细胞中，稳定的β-微管蛋白的延长也会恶化，导致细胞扩散的缺陷。相反，aPKC Zeta缺失小鼠的伤口愈合和定向细胞迁移与其对照小鼠相当。结论：aPKC在功能上不相同；aPKC lambda，而不是aPKC Zeta，在皮肤创伤愈合中起主要作用。(C)2019年日本皮肤研究学会。爱思唯尔出版，版权所有。
Background: The epidermis possesses regenerative properties that become apparent only after wounding. Atypical protein kinase C (aPKC) isoforms aPKC zeta and aPKC lambda form a ternary complex with Par3 and Par6, and play crucial roles in establishing and maintaining epithelial cell polarity. The epidermal loss of aPKC lambda results in progressive depletion of hair follicle stem cells. However, it is unclear whether aPKCs have equivalent activities in epidermal regeneration.Objectives: To clarify functional differences between aPKC zeta and aPKC lambda in cutaneous wound healing.Methods: We compared cutaneous wound healing processes in vivo using mutant mice with genetic deletion of each aPKC isoform. We also analyzed functional differences between aPKC zeta and aPKC lambda in cell proliferation, directional cell migration, and formation of microtubules in vitro using primary keratinocytes established from each mutant mouse.Results: Wound healing was significantly retarded in epidermis-specific aPKC lambda knockout mice. In aPKC lambda deleted keratinocytes, the correct orientation of cell protrusions toward the wound was disrupted through the destabilization of Par6 beta. The elongation of stabilized beta-tubulin was also deteriorated in aPKC lambda-deleted keratinocytes, leading to defects in cell spreading. Conversely, wound healing and directional cell migration in aPKC zeta-deleted mice were comparable to those in their control littermates.Conclusions: aPKCs are not functionally equivalent; aPKC lambda, but not aPKC zeta, plays a primary role in cutaneous wound healing. (C) 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.