Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ

• PKCζ is expressed in Lgr5+ intestinal stem cells
• Loss of PKCζ results in increased intestinal stem cell activity
• PKCζ deficiency in intestinal stem cells drives regeneration and tumorigenesis
• PKCζ reduces β-catenin and Yap levels and function by direct phosphorylation

SummaryIntestinal 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. Protein kinase C ζ (PKCζ) has been previously demonstrated to be a negative regulator of intestinal tumorigenesis. Here, we show 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.

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