Lats1/2 Sustain Intestinal Stem Cells and Wnt Activation through TEAD-Dependent and Independent Transcription

Intestinal homeostasis is tightly controlled by complex yet poorly understood signaling systems. Here, we show Lats1/2, the main Hippo kinases, are crucial to keep Wnt path activity and intestinal stem cells. Lats1/2 deletion results in lack of intestinal stem cells but drives Wnt-uncoupled crypt expansion. Look around the purpose of downstream transcriptional enhanced affiliate domain (TEAD) transcription factors, we identified a selective small-molecule reversible inhibitor of TEAD auto-palmitoylation that directly occupies its fat-binding site and inhibits TEAD-mediated transcription in vivo. Mixing this chemical tool with genetic and proteomics approaches, we reveal that intestinal Wnt inhibition by Lats deletion is absolutely-connected protein (YAP)/transcriptional activator with PDZ-binding domain (TAZ) dependent but TEAD independent. Mechanistically, nuclear YAP/TAZ communicate with Groucho/Transducin-Like Enhancer of Split (TLE) to bar Wnt/T-cell factor (TCF)-mediated transcription, and dual inhibition of TEAD and Lats suppresses Wnt-uncoupled Myc upregulation and epithelial over-proliferation in Adenomatous polyposis coli (APC)-mutated intestine. Our studies highlight a medicinal method of hinder TEAD palmitoylation and also have MGH-CP1 important implications for targeting Wnt and Hippo signaling in human malignancies.