Dermatology, University of Sydney, Australia.
Int J Biochem Cell Biol. 2010 Dec;42(12):1940-4. doi: 10.1016/j.biocel.2010.08.021. Epub 2010 Sep 15.
Keratinocytes are the cells in vertebrates that form the frontline barrier to the environment, and are also the most common origin of human cancer. They normally retain tight cell-cell adhesion and low motility, allowing them to terminally differentiate as they stratify. However, they must be able to respond to tissue damage by migrating into and across wounds. This requires reduced mutual adhesion, suppressed terminal differentiation and increased motility, processes driven by the Snail family of transcriptional repressors. The quantity, location and activity of Snail proteins are regulated by growth factors and cytokines to mediate these responses and invoke an inflammatory response. Subversion of these same pathways can promote carcinoma invasion and metastasis. Signaling network facts: • Snail1 and Snail2 in keratinocytes are important in promoting migration, inflammation and carcinogenesis, and suppressing terminal differentiation. • Extracellular stimuli, including TGFR and EGFR ligands, regulate Snails transcriptionally, via SMAD and MAPK pathways, and post-translationally, by modulating GSK3 and PAK1 activity, which determine Snail stability and intracellular location. • Snails directly repress transcription of genes important for cell-cell adhesion and cornified envelope formation. • Down-regulation of epithelial cadherins by Snails allows LIMDPs to relocate from adherens junctions to the cytoplasm, where they stimulate MAPK pathways, and to the nucleus, where they bind directly to Snails and act as corepressors. • Snail2 is essential for re-epithelialization of healing wounds and can be up-regulated in the keratinocytes at wound margins by p38, ERK1/2 and ERK5 MAPKs, and the arylhydrocarbon receptor. • Further information on signaling related to Snail proteins can be found online at KEGG: http://www.genome.jp/kegg-bin/show pathway?hsa04520 http://www.genome.jp/kegg-bin/show_pathway?hsa04350 http://www.genome.jp/kegg-bin/show pathway?hsa04012.
角朊细胞是脊椎动物中形成环境前线屏障的细胞，也是人类癌症最常见的起源。它们通常保持紧密的细胞间粘附和低迁移能力，使其在分层时终末分化。然而，它们必须能够通过迁移到和穿过伤口来响应组织损伤。这需要减少相互粘附、抑制终末分化和增加迁移能力，这些过程由转录阻遏物 Snail 家族驱动。Snail 蛋白的数量、位置和活性受生长因子和细胞因子的调节，以介导这些反应并引发炎症反应。这些相同途径的颠覆会促进癌的侵袭和转移。信号网络事实：
角朊细胞中的 Snail1 和 Snail2 对于促进迁移、炎症和癌变以及抑制终末分化很重要。
包括 TGFR 和 EGFR 配体在内的细胞外刺激物通过 SMAD 和 MAPK 途径转录调节 Snails，通过调节 GSK3 和 PAK1 活性来调节 Snail 的稳定性和细胞内位置。
Snails 直接抑制细胞间粘附和角蛋白包膜形成的重要基因的转录。
Snails 下调上皮钙黏蛋白，使 LIMDPs 从粘着连接重新定位到细胞质，在细胞质中它们刺激 MAPK 途径，并定位到细胞核，在细胞核中它们直接与 Snails 结合并作为核心抑制物。
Snail2 对角化细胞再生伤口的再上皮化至关重要，并且可以通过 p38、ERK1/2 和 ERK5 MAPKs 和芳香烃受体在伤口边缘的角朊细胞中上调。
有关 Snail 蛋白信号的更多信息可在线获得KEGG：http://www.genome.jp/kegg-bin/show pathway?hsa04520 http://www.genome.jp/kegg-bin/show_pathway?hsa04350 http://www.genome.jp/kegg-bin/show pathway?hsa04012。
