C‐terminal Src kinase controls development and maintenance of mouse squamous epithelia
C‐terminal Src kinase controls development and maintenance of mouse squamous epithelia
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DOI：
10.1038/sj.emboj.7601595
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发表时间：
2007-03
期刊：
影响因子：
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通讯作者：
R. Yagi;S. Waguri;Y. Sumikawa;S. Nada;Chitose Oneyama;S. Itami;C. Schmedt;Y. Uchiyama;M. Okada
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文献类型：
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作者：
R. Yagi;S. Waguri;Y. Sumikawa;S. Nada;Chitose Oneyama;S. Itami;C. Schmedt;Y. Uchiyama;M. Okada
羧基末端Src激酶（Csk）是Src家族激酶的负调控因子，在控制细胞粘附、迁移和癌症进展中起关键作用。为了阐明Csk在上皮组织中的作用，我们使用角蛋白- 5启动子/Cre - loxP系统在小鼠鳞状上皮中条件灭活了Csk。突变小鼠在皮肤、食道和前胃出现明显缺陷，并伴有增生和慢性炎症。突变表皮的组织学显示基底细胞层的细胞粘附受损。对原代角质形成细胞的分析表明，缺陷细胞-细胞粘附是由激活Rac1通路的细胞骨架重塑引起的。突变的角质形成细胞也表现出间充质蛋白、基质金属蛋白酶（MMPs）和促炎细胞因子TNF‐α的表达升高。抗炎试剂FK506抑制TNF - α和MMP9的表达可治愈表皮增生，提示炎症与表皮增生之间存在因果关系。这些观察结果表明，Src/Csk回路通过控制细胞骨架组织以及与炎症事件相关的表型转换，在上皮的发育和维持中起着至关重要的作用。
Carboxy‐terminal Src kinase (Csk) is a negative regulator of Src family kinases, which play pivotal roles in controlling cell adhesion, migration, and cancer progression. To elucidate thein vivorole of Csk in epithelial tissues, we conditionally inactivated Csk in squamous epithelia using the keratin‐5 promoter/Cre‐loxP system in mice. The mutant mice developed apparent defects in the skin, esophagus, and forestomach, with concomitant hyperplasia and chronic inflammation. Histology of the mutant epidermis revealed impaired cell–cell adhesion in basal cell layers. Analysis of primary keratinocytes showed that the defective cell–cell adhesion was caused by cytoskeletal remodeling via activation of the Rac1 pathway. Mutant keratinocytes also showed elevated expression of mesenchymal proteins, matrix metalloproteinases (MMPs), and the proinflammatory cytokine TNF‐α. Inhibition of the expression of TNF‐α and MMP9 by the anti‐inflammatory reagent FK506 could cure the epidermal hyperplasia, suggesting a causal link between inflammation and epidermal hyperplasia. These observations demonstrate that the Src/Csk circuit plays crucial roles in development and maintenance of epithelia by controlling cytoskeletal organization as well as phenotypic conversion linked to inflammatory events.