YAP/TAZ Are Mechanoregulators of TGF--Smad Signaling and Renal Fibrogenesis

Overview

Journal J Am Soc Nephrol

Specialty Nephrology

Date 2016 Mar 11

PMID 26961347

Citations 205

Authors

Stephen G Szeto

Masahiro Narimatsu

Mingliang Lu

Xiaolin He

Ahmad M Sidiqi

Monica F Tolosa

Lauren Chan

Krystale De Freitas

Janne Folke Bialik

Syamantak Majumder

Stellar Boo

Boris Hinz

Qinghong Dan

Andrew Advani

Rohan John

Jeffrey L Wrana

Andras Kapus

Darren A Yuen

Affiliations

Soon will be listed here.

Abstract

Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF- responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF- In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF--induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF- stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF- to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF- signaling and renal fibrogenesis.

Citing Articles

Inhibition of the Hippo pathway by verteporfin reduces the proliferation and stemness of rat hair follicle neural crest stem cells under hypoxia.

Liu W, Chen S, Chen X, Xue L, Wang Y, Yang J FASEB Bioadv. 2025; 7(3):e70000.

PMID: 40060945 PMC: 11886604. DOI: 10.1096/fba.2025-00025.

A first-in-human study of quantitative ultrasound to assess transplant kidney fibrosis.

Hysi E, Baek J, Koven A, He X, Ulloa Severino L, Wu Y Nat Med. 2025; .

PMID: 40033112 DOI: 10.1038/s41591-024-03417-5.

Mechanosignaling via Integrins: Pivotal Players in Liver Fibrosis Progression and Therapy.

Sharip A, Kunz J Cells. 2025; 14(4).

PMID: 39996739 PMC: 11854242. DOI: 10.3390/cells14040266.

Stiffness Regulates the Morphology and Stemness of Limbal Niche Cells Through Unique nYAP/cYAP Translocation.

Zhou X, Xu L, Tan Y, Wang W, Huang X, Li G Invest Ophthalmol Vis Sci. 2025; 66(2):43.

PMID: 39951297 PMC: 11824500. DOI: 10.1167/iovs.66.2.43.

Role of Hippo-YAP/TAZ signaling pathway in organ fibrosis.

Wang J, Huang L, Yu H, Liu J, Yuan L, Li F Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2025; 49(9):1509-1516.

PMID: 39931781 PMC: 11814394. DOI: 10.11817/j.issn.1672-7347.2024.230577.

References

Zhou Y, Huang X, Hecker L, Kurundkar D, Kurundkar A, Liu H . Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis. J Clin Invest. 2013; 123(3):1096-108. PMC: 3582144. DOI: 10.1172/JCI66700. View

Kandow C, Georges P, Janmey P, Beningo K . Polyacrylamide hydrogels for cell mechanics: steps toward optimization and alternative uses. Methods Cell Biol. 2007; 83:29-46. DOI: 10.1016/S0091-679X(07)83002-0. View

Tomasek J, Gabbiani G, Hinz B, Chaponnier C, Brown R . Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002; 3(5):349-63. DOI: 10.1038/nrm809. View

Beyer T, Weiss A, Khomchuk Y, Huang K, Ogunjimi A, Varelas X . Switch enhancers interpret TGF-β and Hippo signaling to control cell fate in human embryonic stem cells. Cell Rep. 2013; 5(6):1611-24. DOI: 10.1016/j.celrep.2013.11.021. View

Huang X, Yang N, Fiore V, Barker T, Sun Y, Morris S . Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction. Am J Respir Cell Mol Biol. 2012; 47(3):340-8. PMC: 3488695. DOI: 10.1165/rcmb.2012-0050OC. View

Godbout C, Follonier Castella L, Smith E, Talele N, Chow M, Garonna A . The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts. PLoS One. 2013; 8(5):e64560. PMC: 3653915. DOI: 10.1371/journal.pone.0064560. View

Donohue E, Balgi A, Komatsu M, Roberge M . Induction of Covalently Crosslinked p62 Oligomers with Reduced Binding to Polyubiquitinated Proteins by the Autophagy Inhibitor Verteporfin. PLoS One. 2014; 9(12):e114964. PMC: 4262463. DOI: 10.1371/journal.pone.0114964. View

LeBleu V, Taduri G, OConnell J, Teng Y, Cooke V, Woda C . Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013; 19(8):1047-53. PMC: 4067127. DOI: 10.1038/nm.3218. View

Shi Y, Massague J . Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003; 113(6):685-700. DOI: 10.1016/s0092-8674(03)00432-x. View

10.

Wilkinson D . RNA detection using non-radioactive in situ hybridization. Curr Opin Biotechnol. 1995; 6(1):20-3. DOI: 10.1016/0958-1669(95)80004-2. View

11.

Fine L, Norman J . Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int. 2008; 74(7):867-72. DOI: 10.1038/ki.2008.350. View

12.

Swift J, Ivanovska I, Buxboim A, Harada T, Dingal P, Pinter J . Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science. 2013; 341(6149):1240104. PMC: 3976548. DOI: 10.1126/science.1240104. View

13.

Arndt R, Schmidt S, Loddenkemper C, Grunbaum M, Zidek W, van der Giet M . Noninvasive evaluation of renal allograft fibrosis by transient elastography--a pilot study. Transpl Int. 2010; 23(9):871-7. DOI: 10.1111/j.1432-2277.2010.01057.x. View

14.

Rauskolb C, Sun S, Sun G, Pan Y, Irvine K . Cytoskeletal tension inhibits Hippo signaling through an Ajuba-Warts complex. Cell. 2014; 158(1):143-156. PMC: 4082802. DOI: 10.1016/j.cell.2014.05.035. View

15.

Codelia V, Sun G, Irvine K . Regulation of YAP by mechanical strain through Jnk and Hippo signaling. Curr Biol. 2014; 24(17):2012-7. PMC: 4160395. DOI: 10.1016/j.cub.2014.07.034. View

16.

Zhang H, Ramakrishnan S, Triner D, Centofanti B, Maitra D, Gyorffy B . Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1. Sci Signal. 2015; 8(397):ra98. PMC: 4818013. DOI: 10.1126/scisignal.aac5418. View

17.

Attisano L, Wrana J . Signal transduction by the TGF-beta superfamily. Science. 2002; 296(5573):1646-7. DOI: 10.1126/science.1071809. View

18.

Yuen D, Connelly K, Advani A, Liao C, Kuliszewski M, Trogadis J . Culture-modified bone marrow cells attenuate cardiac and renal injury in a chronic kidney disease rat model via a novel antifibrotic mechanism. PLoS One. 2010; 5(3):e9543. PMC: 2832011. DOI: 10.1371/journal.pone.0009543. View

19.

Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez H, Oyasu M . Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med. 2010; 16(9):1009-17. DOI: 10.1038/nm.2208. View

20.

Liu-Chittenden Y, Huang B, Shim J, Chen Q, Lee S, Anders R . Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012; 26(12):1300-5. PMC: 3387657. DOI: 10.1101/gad.192856.112. View