PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis

Katherine Martin, James Pritchett, Jessica Llewellyn, Aoibheann F. Mullan, Varinder S. Athwal, Ross Dobie, Emma Harvey, Leo Zeef, Stuart Farrow, Charles Streuli, Neil C. Henderson, Scott L. Friedman, Neil A. Hanley () and Karen Piper Hanley ()
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Katherine Martin: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
James Pritchett: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Jessica Llewellyn: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Aoibheann F. Mullan: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Varinder S. Athwal: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Ross Dobie: MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh
Emma Harvey: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Leo Zeef: Bioinformatics Core Facility, Faculty of Life Sciences, University of Manchester
Stuart Farrow: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Charles Streuli: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester
Neil C. Henderson: MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh
Scott L. Friedman: Icahn School of Medicine at Mount Sinai
Neil A. Hanley: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre
Karen Piper Hanley: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis.

Date: 2016
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DOI: 10.1038/ncomms12502

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