title: PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis.
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.
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Research and Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Martin
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Research and Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: James
authors.identifier: 0000-0003-2620-7061
authors.initials: J
authors.lastname: Pritchett
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Llewellyn
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: Aoibheann F
authors.initials: AF
authors.lastname: Mullan
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Research and Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Varinder S
authors.initials: VS
authors.lastname: Athwal
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Dobie
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Harvey
authors.affiliation: Bioinformatics Core Facility, Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Leo
authors.initials: L
authors.lastname: Zeef
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Respiratory Therapy Area, GlaxoSmithKline, Stevenage SG1 2NY, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Farrow
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Streuli
authors.affiliation: MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Henderson
authors.affiliation: Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Research and Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hanley
authors.affiliation: Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.|Research and Innovation Division, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WU, UK.
authors.forename: Karen
authors.identifier: 0000-0001-9473-9647
authors.initials: K
authors.lastname: Piper Hanley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D055166:Hepatic Stellate Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology*; D018994:Myosin Light Chains / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019012:Integrin beta1; D018994:Myosin Light Chains; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D054462:p21-Activated Kinases