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      Caveolin-1 Modulates Mechanotransduction Responses to Substrate Stiffness through Actin-Dependent Control of YAP

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          Summary

          The transcriptional regulator YAP orchestrates many cellular functions, including tissue homeostasis, organ growth control, and tumorigenesis. Mechanical stimuli are a key input to YAP activity, but the mechanisms controlling this regulation remain largely uncharacterized. We show that CAV1 positively modulates the YAP mechanoresponse to substrate stiffness through actin-cytoskeleton-dependent and Hippo-kinase-independent mechanisms. RHO activity is necessary, but not sufficient, for CAV1-dependent mechanoregulation of YAP activity. Systematic quantitative interactomic studies and image-based small interfering RNA (siRNA) screens provide evidence that this actin-dependent regulation is determined by YAP interaction with the 14-3-3 protein YWHAH. Constitutive YAP activation rescued phenotypes associated with CAV1 loss, including defective extracellular matrix (ECM) remodeling. CAV1-mediated control of YAP activity was validated in vivo in a model of pancreatitis-driven acinar-to-ductal metaplasia. We propose that this CAV1-YAP mechanotransduction system controls a significant share of cell programs linked to these two pivotal regulators, with potentially broad physiological and pathological implications.

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          Highlights

          • •

            CAV1 modulates YAP activity in response to changes in ECM stiffness

          • •

            CAV1 regulates YAP through the control of actin dynamics and YAP phosphorylation

          • •

            YWHAH-YAP interaction blunts YAP activity in CAV1-deficient cells

          • •

            CAV1-YAP mechanotransduction drives ECM remodeling and pancreatic ADM

          Abstract

          Moreno-Vicente et al. report that CAV1, a key component of PM mechanosensing caveolae, mediates adaptation to ECM rigidity by modulating YAP activity through the control of actin dynamics and phosphorylation-dependent interaction of YAP with the 14-3-3-domain protein YWHAH. Cav1-dependent YAP regulation drives two pathophysiological processes: ECM remodeling and pancreatic ADM.

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          Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.

          Carmen Guerra, Alberto J Schuhmacher, Marta Cañamero … (2007)
          Pancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes. We report that selective expression of an endogenous K-Ras(G12V) oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-Ras(G12V)-induced PanINs and PDA. However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.
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            Cells respond to mechanical stress by rapid disassembly of caveolae.

            Bidisha Sinha, Darius Köster, Richard Ruez … (2011)
            The functions of caveolae, the characteristic plasma membrane invaginations, remain debated. Their abundance in cells experiencing mechanical stress led us to investigate their role in membrane-mediated mechanical response. Acute mechanical stress induced by osmotic swelling or by uniaxial stretching results in a rapid disappearance of caveolae, in a reduced caveolin/Cavin1 interaction, and in an increase of free caveolins at the plasma membrane. Tether-pulling force measurements in cells and in plasma membrane spheres demonstrate that caveola flattening and disassembly is the primary actin- and ATP-independent cell response that buffers membrane tension surges during mechanical stress. Conversely, stress release leads to complete caveola reassembly in an actin- and ATP-dependent process. The absence of a functional caveola reservoir in myotubes from muscular dystrophic patients enhanced membrane fragility under mechanical stress. Our findings support a new role for caveolae as a physiological membrane reservoir that quickly accommodates sudden and acute mechanical stresses. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Preparation of hydrogel substrates with tunable mechanical properties.

              Justin Tse, Adam Engler (2010)
              The modulus of elasticity of the extracellular matrix (ECM), often referred to in a biological context as "stiffness," naturally varies within the body, e.g., hard bones and soft tissue. Moreover, it has been found to have a profound effect on the behavior of anchorage-dependent cells. The fabrication of matrix substrates with a defined modulus of elasticity can be a useful technique to study the interactions of cells with their biophysical microenvironment. Matrix substrates composed of polyacrylamide hydrogels have an easily quantifiable elasticity that can be changed by adjusting the relative concentrations of its monomer, acrylamide, and cross-linker, bis-acrylamide. In this unit, we detail a protocol for the fabrication of statically compliant and radial-gradient polyacrylamide hydrogels, as well as the functionalization of these hydrogels with ECM proteins for cell culture. Included as well are suggestions to optimize this protocol to the choice of cell type or stiffness with a table of relative bis-acrylamide and acrylamide concentrations and expected elasticity after polymerization.
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                Author and article information

                Contributors
                Miguel A. del Pozo
                Journal
                Journal ID (nlm-ta): Cell Rep
                Journal ID (iso-abbrev): Cell Rep
                Title: Cell Reports
                Publisher: Cell Press
                ISSN (Electronic): 2211-1247
                Publication date PMC-release: 06 November 2018
                Publication date Collection: 06 November 2018
                Publication date (Electronic): 06 November 2018
                Volume: 25
                Issue: 6
                Pages: 1622-1635.e6
                Affiliations
                [1 ]Mechanoadaptation & Caveolae Biology Lab, Cell and Developmental Biology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
                [2 ]Cardiovascular Proteomics Unit, CNIC, Madrid 28029, Spain
                [3 ]Section of Molecular Genetics, Department of Cellular Biotechnologies and Hematology, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome 00161, Italy
                Author notes
                [∗ ]Corresponding author madelpozo@ 123456cnic.es
                [4]

                Lead Contact

                Article
                Publisher ID: S2211-1247(18)31600-0
                DOI: 10.1016/j.celrep.2018.10.024
                PMC ID: 6231326
                PubMed ID: 30404014
                SO-VID: ddd0f98e-c5d7-47bd-a131-ac700f4dd361
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 1 March 2018
                Date revision received : 16 August 2018
                Date accepted : 3 October 2018
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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