From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan and.
From the Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan and
J Biol Chem. 2018 Jun 1;293(22):8342-8361. doi: 10.1074/jbc.RA117.000992. Epub 2018 Apr 19.
Epithelia contribute to physical barriers that protect internal tissues from the external environment and also support organ structure. Accordingly, establishment and maintenance of epithelial architecture are essential for both embryonic development and adult physiology. Here, using gene knockout and knockdown techniques along with gene profiling, we show that extracellular signal-regulated kinase 3 (ERK3), a poorly characterized atypical mitogen-activated protein kinase (MAPK), regulates the epithelial architecture in vertebrates. We found that in embryonic epidermal epithelia, knockdown impairs adherens and tight-junction protein distribution, as well as tight-junction barrier function, resulting in epidermal breakdown. Moreover, in human epithelial breast cancer cells, inhibition of expression induced thickened epithelia with aberrant adherens and tight junctions. Results from microarray analyses suggested that transcription factor AP-2α (TFAP2A), a transcriptional regulator important for epithelial gene expression, is involved in ERK3-dependent changes in gene expression. Of note, knockdown phenocopied knockdown in both embryos and human cells, and was required for full activation of TFAP2A-dependent transcription. Our findings reveal that ERK3 regulates epithelial architecture, possibly together with TFAP2A.
上皮组织有助于形成物理屏障，保护内部组织免受外部环境的影响，并为器官结构提供支持。因此，上皮结构的建立和维持对于胚胎发育和成人生理学都是至关重要的。在这里，我们使用基因敲除和敲低技术以及基因谱分析，表明细胞外信号调节激酶 3（ERK3），一种特征不明显的丝裂原活化蛋白激酶（MAPK），调节脊椎动物的上皮结构。我们发现，在胚胎表皮上皮中，敲低会损害黏附连接和紧密连接蛋白的分布，以及紧密连接的屏障功能，导致表皮破裂。此外，在人类上皮乳腺癌细胞中，抑制表达会诱导上皮细胞变厚，出现黏附连接和紧密连接异常。微阵列分析的结果表明，转录因子 AP-2α（TFAP2A）是一种对上皮基因表达很重要的转录调节因子，参与了 ERK3 依赖性的基因表达变化。值得注意的是，在胚胎和人类细胞中，敲低均能模拟敲低，并且完全激活 TFAP2A 依赖性转录需要。我们的研究结果表明，ERK3 可能与 TFAP2A 一起调节上皮结构。
