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Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling
Author(s) -
Xu Jiuzhi,
Tang Yang,
Sheng Xiaole,
Tian Yuhua,
Deng Min,
Du Sujuan,
Lv Cong,
Li Guili,
Pan Yuwei,
Song Yongli,
Lou Pengbo,
Luo Yongting,
Li Yuan,
Zhang Bing,
Chen Yanmei,
Liu Zhanju,
Cong Yingzi,
Plikus Maksim V,
Meng Qingyong,
Zhou Zhaocai,
Yu Zhengquan
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103255
Subject(s) - biology , hippo signaling pathway , microbiology and biotechnology , stromal cell , regeneration (biology) , signal transduction , intestinal epithelium , epithelium , cancer research , genetics
The Hippo–YAP signaling pathway plays an essential role in epithelial cells during 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–epithelium ISLR–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 inhibit Hippo signaling and activate YAP in epithelial cells. 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 provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.