IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells

Anissa A Widjaja; Sivakumar Viswanathan; Joyce Goh Wei Ting; Jessie Tan; Shamini G Shekeran; David Carling; Wei-Wen Lim; Stuart A Cook

doi:10.1016/j.isci.2022.104806

IL11 stimulates ERK/P90RSK to inhibit LKB1/AMPK and activate mTOR initiating a mesenchymal program in stromal, epithelial, and cancer cells

iScience. 2022 Jul 20;25(8):104806. doi: 10.1016/j.isci.2022.104806. eCollection 2022 Aug 19.

Authors

Anissa A Widjaja¹, Sivakumar Viswanathan¹, Joyce Goh Wei Ting¹, Jessie Tan², Shamini G Shekeran¹, David Carling³, Wei-Wen Lim^{1

2}, Stuart A Cook^{1

2

3}

Affiliations

¹ Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore 169857, Singapore.
² National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore.
³ MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W12 0NN, UK.

Abstract

IL11 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.

Keywords: Cell biology; Functional aspects of cell biology.

Abstract

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