NDR Functions as a Physiological YAP1 Kinase in the Intestinal Epithelium

• Published in: Current biology Vol. 25; no. 3; pp. 296 - 305
• Main Authors: Zhang, Lei, Tang, Fengyuan, Terracciano, Luigi, Hynx, Debby, Kohler, Reto, Bichet, Sandrine, Hess, Daniel, Cron, Peter, Hemmings, Brian A., Hergovich, Alexander, Schmitz-Rohmer, Debora
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 02.02.2015; Cell Press
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Blotting, Western; Cell Cycle Proteins; Cell Proliferation; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - physiology; Histological Techniques; Humans; Intestinal Mucosa - enzymology; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Phosphoproteins - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Serine - metabolism
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2014.11.054

Phosphorylation of the transcriptional coactivator YAP1 is a key event in defining Hippo signaling outputs. Previous studies demonstrated that phosphorylation of YAP1 at serine 127 (S127) sequesters YAP1 in the cytoplasm and consequently inhibits YAP1 transcriptional activity. Mammalian tissue-culture experiments suggest that downstream of MST1/2 signaling, LATS1/2 function as YAP1-S127 kinases. However, studies of Mst1/2 knockout mouse models revealed that the identity of the physiological YAP1-S127 kinase(s) in certain tissues, such as the intestine, remains unknown. We show that mammalian NDR1/2 kinases phosphorylate YAP1 on S127 and thereby negatively regulate YAP1 activity in tissue-cultured cells. By studying NDR1/2-deficient mice, we demonstrate the in vivo relevance of NDR1/2-mediated regulation of YAP1. Specifically, upon loss of NDR1/2 in the intestinal epithelium, endogenous S127 phosphorylation is decreased whereas total YAP1 levels are increased. Significantly, ablation of NDR1/2 from the intestinal epithelium renders mice exquisitely sensitive to chemically induced colon carcinogenesis. Analysis of human colon cancer samples further revealed that NDR2 and YAP1 protein expression are inversely correlated in the majority of samples with high YAP1 expression. Collectively, we report NDR1/2 as physiological YAP1-S127 kinases that might function as tumor suppressors upstream of YAP1 in human colorectal cancer. We establish mammalian NDR1/2 as bona fide kinases that target YAP1 on S127 in vitro and in vivo. Our findings therefore have important implications for a broad range of research efforts aimed at decoding and eventually manipulating YAP1 biology in cancer settings, regenerative medicine, and possibly also noncancer human diseases. [Display omitted] •Mammalian NDR kinases phosphorylate YAP1 on serine 127•Phosphorylation of YAP1 by NDR kinases regulates YAP1 activity in vivo•NDR kinases function as tumor suppressors in the intestinal epithelium•Ndr knockout mice represent the first animal model of a direct S127 kinase Phosphorylation of the Hippo pathway effector YAP1 contributes to tissue homeostasis. However, the identity of the YAP1 kinase in the intestine remains unknown. Here, Zhang et al. report NDR as a physiological YAP1 kinase, restricting YAP1’s activity in the intestine and hence establishing the first mouse model of a direct YAP1-S127 kinase.