TY - JOUR T1 - Stromal ISLR promotes intestinal regeneration and cancer by suppressing epithelial Hippo signaling via FAT1 JF - bioRxiv DO - 10.1101/740472 SP - 740472 AU - Jiuzhi Xu AU - Yang Tang AU - Xiaole Sheng AU - Yuhua Tian AU - Min Deng AU - Sujuan Du AU - Cong Lv AU - Yongli Song AU - Pengbo Lou AU - Yongting Luo AU - Yuan Li AU - Bing Zhang AU - Yanmei Chen AU - Zhanju Liu AU - Yingzi Cong AU - Maksim V. Plikus AU - Qingyong Meng AU - Zhaocai Zhou AU - Zhengquan Yu Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/20/740472.abstract N2 - The YAP signaling activation in epithelial cells is essential for intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here we report a stroma-epithelia YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can directly binds to a transmembrane protocadherin FAT1 on the surface of epithelial cells. This binding suppressed the Hippo signaling by disrupting MST1-FAT1 association, resulting in YAP signaling activation. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration, and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings uncovered a molecular mechanism governing signals for communication between stroma and epithelium during tissue regeneration and tumorigenesis. ER -