Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis
- PMID: 25502501
- PMCID: PMC4329470
- DOI: 10.1152/ajplung.00300.2014
Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis
Abstract
Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.
Keywords: Hippo; extracellular matrix; idiopathic pulmonary fibrosis; mechanotransduction; plasminogen activator inhibitor 1.
Copyright © 2015 the American Physiological Society.
Figures
![Fig. 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870001.gif)
![Fig. 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870002.gif)
![Fig. 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870003.gif)
![Fig. 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870004.gif)
![Fig. 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870005.gif)
![Fig. 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870006.gif)
![Fig. 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870007.gif)
![Fig. 8.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4329470/bin/zh50051566870008.gif)
Similar articles
-
TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation.Am J Physiol Lung Cell Mol Physiol. 2020 May 1;318(5):L852-L863. doi: 10.1152/ajplung.00324.2019. Epub 2020 Mar 11. Am J Physiol Lung Cell Mol Physiol. 2020. PMID: 32159970 Free PMC article.
-
Therapeutic Targeting of TAZ and YAP by Dimethyl Fumarate in Systemic Sclerosis Fibrosis.J Invest Dermatol. 2018 Jan;138(1):78-88. doi: 10.1016/j.jid.2017.08.024. Epub 2017 Sep 1. J Invest Dermatol. 2018. PMID: 28870693 Free PMC article.
-
YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer.Int J Mol Sci. 2018 Nov 20;19(11):3674. doi: 10.3390/ijms19113674. Int J Mol Sci. 2018. PMID: 30463366 Free PMC article. Review.
-
TAZ Protein Accumulation Is Negatively Regulated by YAP Abundance in Mammalian Cells.J Biol Chem. 2015 Nov 13;290(46):27928-38. doi: 10.1074/jbc.M115.692285. Epub 2015 Oct 2. J Biol Chem. 2015. PMID: 26432639 Free PMC article.
-
Multifaceted regulation and functions of YAP/TAZ in tumors (Review).Oncol Rep. 2018 Jul;40(1):16-28. doi: 10.3892/or.2018.6423. Epub 2018 May 8. Oncol Rep. 2018. PMID: 29749524 Free PMC article. Review.
Cited by
-
Triple click chemistry for crosslinking, stiffening, and annealing of gelatin-based microgels.RSC Appl Polym. 2024 Mar 28;2(4):656-669. doi: 10.1039/d3lp00249g. eCollection 2024 Jul 18. RSC Appl Polym. 2024. PMID: 39035826 Free PMC article.
-
Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells.Cell Commun Signal. 2024 May 27;22(1):289. doi: 10.1186/s12964-024-01662-2. Cell Commun Signal. 2024. PMID: 38802925 Free PMC article. Review.
-
SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment.Cells. 2024 May 7;13(10):796. doi: 10.3390/cells13100796. Cells. 2024. PMID: 38786020 Free PMC article. Review.
-
Drugs targeting CTGF in the treatment of pulmonary fibrosis.J Cell Mol Med. 2024 May;28(10):e18448. doi: 10.1111/jcmm.18448. J Cell Mol Med. 2024. PMID: 38774993 Free PMC article. Review.
-
The role of yes activated protein (YAP) in melanoma metastasis.iScience. 2024 Apr 30;27(6):109864. doi: 10.1016/j.isci.2024.109864. eCollection 2024 Jun 21. iScience. 2024. PMID: 38770136 Free PMC article. Review.
References
-
- Abe M, Harpel JG, Metz CN, Nunes I, Loskutoff DJ, Rifkin DB. An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal Biochem 216: 276–284, 1994. - PubMed
-
- Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154: 1047–1059, 2013. - PubMed
-
- Balestrini JL, Chaudhry S, Sarrazy V, Koehler A, Hinz B. The mechanical memory of lung myofibroblasts. Integr Biol (Camb) 4: 410–421, 2012. - PubMed
-
- Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van Vlasselaer P, Smith V. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 16: 1009–1017, 2010. - PubMed
-
- Beacham DA, Amatangelo MD, Cukierman E. Preparation of extracellular matrices produced by cultured and primary fibroblasts. Curr Protoc Cell Biol 10: 19, 2007. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- DK046200/DK/NIDDK NIH HHS/United States
- HL092961/HL/NHLBI NIH HHS/United States
- R01 HL105489/HL/NHLBI NIH HHS/United States
- HL108975/HL/NHLBI NIH HHS/United States
- HL095732/HL/NHLBI NIH HHS/United States
- R01 HL092961/HL/NHLBI NIH HHS/United States
- R01 HL114839/HL/NHLBI NIH HHS/United States
- HL114839/HL/NHLBI NIH HHS/United States
- HL115106/HL/NHLBI NIH HHS/United States
- HL113796/HL/NHLBI NIH HHS/United States
- HL078871/HL/NHLBI NIH HHS/United States
- P30 DK046200/DK/NIDDK NIH HHS/United States
- R01 HL078871/HL/NHLBI NIH HHS/United States
- R01 HL124392/HL/NHLBI NIH HHS/United States
- T32 EB005583/EB/NIBIB NIH HHS/United States
- HL105489/HL/NHLBI NIH HHS/United States
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous