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

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 beta-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 zeta (PKC zeta) has been previously demonstrated to be a negative regulator of intestinal tumorigenesis. Here, we show that PKC zeta suppresses intestinal stem cell function by promoting the downregulation of beta-catenin and Yap through direct phosphorylation. PKC zeta 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 PKC zeta-deficient mice. This demonstrates that PKC zeta is central to the control of stem cells in intestinal cancer and homeostasis.