Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling

Jiuzhi Xu, Yang Tang, Xiaole Sheng, Yuhua Tian, Min Deng, Sujuan Du, Cong Lv, Guili Li, Yuwei Pan, Yongli Song, Pengbo Lou, Yongting Luo, Yuan Li, Bing Zhang, Yanmei Chen, Zhanju Liu, Yingzi Cong, Maksim V. Plikus, Qingyong Meng, Zhaocai ZhouZhengquan Yu

    Research output: Contribution to journalArticle

    Abstract

    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.

    Original languageEnglish (US)
    Article numbere103255
    JournalEMBO Journal
    Volume39
    Issue number7
    DOIs
    StatePublished - Apr 1 2020

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    Keywords

    • Hippo signaling
    • ISLR
    • colorectal cancer
    • intestinal regeneration
    • stroma–epithelia crosstalk

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Molecular Biology
    • Biochemistry, Genetics and Molecular Biology(all)
    • Immunology and Microbiology(all)

    Cite this

    Xu, J., Tang, Y., Sheng, X., Tian, Y., Deng, M., Du, S., Lv, C., Li, G., Pan, Y., Song, Y., Lou, P., Luo, Y., Li, Y., Zhang, B., Chen, Y., Liu, Z., Cong, Y., Plikus, M. V., Meng, Q., ... Yu, Z. (2020). Secreted stromal protein ISLR promotes intestinal regeneration by suppressing epithelial Hippo signaling. EMBO Journal, 39(7), [e103255]. https://doi.org/10.15252/embj.2019103255