Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ.
Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ.
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DOI：
10.1016/j.celrep.2015.01.007
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发表时间：
2015-02-10
期刊：
影响因子：
8.8
通讯作者：
Moscat J
中科院分区：
文献类型：
--
作者：
Llado V;Nakanishi Y;Duran A;Reina-Campos M;Shelton PM;Linares JF;Yajima T;Campos A;Aza-Blanc P;Leitges M;Diaz-Meco MT;Moscat J
肠上皮稳态需要位于隐窝底部的干细胞的持续更新支持。这种平衡的破坏导致再生失败并引发肿瘤发生。Lgr5+干细胞中的β-catenin和Yap通路已被证明是这一过程的核心。然而，这些信号分子在干细胞群中调控的确切机制尚不完全清楚。PKCζ先前已被证明是肠道肿瘤发生的负调节因子。我们在这里表明PKCζ通过直接磷酸化促进β-catenin和Yap的下调，从而抑制肠道干细胞的功能。PKCζ缺乏导致类器官培养和体内干细胞活性增加，说明Lgr5+特异性PKCζ缺乏小鼠的致瘤性和再生活性反应增加。这表明PKCζ是控制肠癌干细胞和体内平衡的核心。
Intestinal epithelial homeostasis requires continuous renewal supported by stem cells located in the base of the crypt. Disruption of this balance results in failure to regenerate and initiates tumorigenesis. The β-catenin and Yap pathways in Lgr5+ stem cells have been shown to be central to this process. However, the precise mechanisms by which these signaling molecules are regulated in the stem cell population are not totally understood. PKCζ has been previously demonstrated to be a negative regulator of intestinal tumorigenesis. We show here that PKCζ suppresses intestinal stem cell function by promoting the downregulation of β-catenin and Yap through direct phosphorylation. PKCζ deficiency results in increased stem cell activity in organoid cultures and in vivo, accounting for the increased tumorigenic and regenerative activity response of Lgr5+-specific PKCζ-deficient mice. This demonstrates that PKCζ is central to the control of stem cells in intestinal cancer and homeostasis.