title: Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ.
abstract: 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. 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.
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Victoria
authors: V
authors: Llado
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Yuki
authors: Y
authors: Nakanishi
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Angeles
authors: A
authors: Duran
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Miguel
authors: M
authors: Reina-Campos
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Phillip M
authors: PM
authors: Shelton
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Juan F
authors: JF
authors: Linares
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Tomoko
authors: T
authors: Yajima
authors: Proteomics Facility, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Alex
authors: A
authors: Campos
authors: Functional Genomics Core, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Pedro
authors: P
authors: Aza-Blanc
authors: Biotechnology Centre of Oslo, University of Oslo, 0316 Oslo, Norway.
authors: Michael
authors: M
authors: Leitges
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Maria T
authors: MT
authors: Diaz-Meco
authors: Cell Death and Survival Networks Program, Sanford-Burnham Medical Research Institute, 10901 North. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jmoscat@sanfordburnham.org.
authors: Jorge
authors: J
authors: Moscat