文章基本信息

标题：IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells
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作者：Anissa A. Widjaja ; Sivakumar Viswanathan ; Joyce Goh Wei Ting 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：8
页码：1-20
DOI：10.1016/j.isci.2022.104806
语种：English
出版社：Elsevier
摘要：SummaryIL11 initiates fibroblast activation but also causes epithelial cell dysfunction. The mechanisms underlying these processes are not known. We report that IL11-stimulated ERK/P90RSK activity causes the phosphorylation of LKB1 at S325 and S428, leading to its inactivation. This inhibits AMPK and activates mTOR across cell types. In stromal cells, IL11-stimulated ERK activity inhibits LKB1/AMPK which is associated with mTOR activation, ⍺SMA expression, and myofibroblast transformation. In hepatocytes and epithelial cells, IL11/ERK activity inhibits LKB1/AMPK leading to mTOR activation, SNAI1 expression, and cell dysfunction. Across cells, IL11-induced phenotypes were inhibited by metformin stimulated AMPK activation. In mice, genetic or pharmacologic manipulation of IL11 activity revealed a critical role of IL11/ERK signaling for LKB1/AMPK inhibition and mTOR activation in fatty liver disease. These data identify the IL11/mTOR axis as a signaling commonality in stromal, epithelial, and cancer cells and reveal a shared IL11-driven mesenchymal program across cell types.Graphical abstractDisplay OmittedHighlights•How IL11 activates the stroma but causes epithelial dysfunction is not known•IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR•In disease, IL11 causes EMT: damaging the epithelium and activating the stroma•Activation of AMPK with metformin reduces IL11-induced disease phenotypesCell biology; Functional aspects of cell biology