A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth
A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth
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DOI：
10.1038/nature04659
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发表时间：
2006-05-18
期刊：
影响因子：
64.8
通讯作者：
Coulombe, PA
中科院分区：
文献类型：
--
作者：
Kim, S;Wong, P;Coulombe, PA
细胞生长，即质量和大小的增加，是一种高度调节的细胞事件。Akt/mTOR（雷帕霉素的哺乳动物靶蛋白）信号通路在控制蛋白质合成以及细胞、组织和生物体的生长中起着核心作用（1）。需要快速细胞生长的生理背景的一个突出例子是响应于损伤的组织修复（2）。在这里，我们发现角蛋白17，一种在受伤的复层上皮中快速诱导的中间丝蛋白（3），通过与接头蛋白14-3-3 σ结合来调节细胞生长。缺乏角蛋白17的小鼠皮肤角质形成细胞（参考文献4）显示蛋白质翻译降低，尺寸较小，与Akt/mTOR信号传导活性降低相关。其他信号激酶有正常的活动，指出这种缺陷的特异性。位于角蛋白17的氨基末端头部结构域中的两个氨基酸残基是14-3-3 σ从细胞核到细胞质的血清依赖性再定位以及伴随的mTOR活性和细胞生长的刺激所需要的。这些发现揭示了一个新的和意想不到的作用，中间丝细胞骨架在影响细胞生长和大小，通过调节蛋白质合成。
Cell growth, an increase in mass and size, is a highly regulated cellular event. The Akt/mTOR ( mammalian target of rapamycin) signalling pathway has a central role in the control of protein synthesis and thus the growth of cells, tissues and organisms(1). A striking example of a physiological context requiring rapid cell growth is tissue repair in response to injury(2). Here we show that keratin 17, an intermediate filament protein rapidly induced in wounded stratified epithelia(3), regulates cell growth through binding to the adaptor protein 14-3-3 sigma. Mouse skin keratinocytes lacking keratin 17 (ref. 4) show depressed protein translation and are of smaller size, correlating with decreased Akt/mTOR signalling activity. Other signalling kinases have normal activity, pointing to the specificity of this defect. Two amino acid residues located in the amino-terminal head domain of keratin 17 are required for the serum-dependent relocalization of 14-3-3 sigma from the nucleus to the cytoplasm, and for the concomitant stimulation of mTOR activity and cell growth. These findings reveal a new and unexpected role for the intermediate filament cytoskeleton in influencing cell growth and size by regulating protein synthesis.