Restriction of intestinal stem cell expansion and the regenerative response by YAP

YAP has previously been identified as an oncogene that promotes cell growth, but now it is shown to restrict stem cell expansion during regeneration in the mouse intestine, suggesting that it may function as a tumour suppressor in colon cancer. Conflicting growth effects of YAP protein YAP is the main transcriptional effector of the growth-suppressive Hippo signalling pathway. It has been identified as an oncogene that promotes cell growth, and has emerged as a potential antitumour target. Surprisingly, Fernando Camargo and colleagues now find that in the mouse intestine, YAP actually suppresses growth, acting to restrict stem cell expansion during regeneration by limiting Wnt signalling. Consequently, loss of YAP leads to hyperplasia and microadenomas during regeneration. YAP is found to be downregulated in some human colon cancer, and its expression can reduce the growth of human colorectal cancer xenografts, suggesting that it may function as a tumour suppressor in colon cancer. A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)—a protein known for its powerful growth-inducing and oncogenic properties 1 , 2 —has an unexpected growth-suppressive function, restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signalling independently of the AXIN–APC–GSK-3β complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the