Role of YAP/TAZ in mechanotransduction

Abstract

Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.

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Figure 1: YAP/TAZ are regulated by ECM stiffness and cell shape
Figure 2: YAP/TAZ activity requires Rho and tension of the actin cytoskeleton
Figure 3: ECM stiffness and cell spreading regulate YAP/TAZ independently of the Hippo pathway
Figure 4: YAP/TAZ are required mediators of the biological effects controlled by ECM elasticity and cell geometry

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Acknowledgements

We thank G. Scita for advice and gift of reagents; X. Yang for 5SA-YAP1 plasmid; I. Farrance for 4×GTIIC-lux plasmid; H. Miyoshi for pCSII-EF-MCS vector; L. Naldini for pMD2-VSVG vector; R. Treisman for ΔN1+C mDIA, R26D and V159N Actin plasmids; G. Posern for SRF-lux reporter; mouse TAZ and psPAX2 were Addgene plasmid 19025 and 12260. This work was supported by: Telethon and Progetti di Eccellenza CARIPARO grants to N.E.; AIRC (Italian Association for Cancer Research) PI and AIRC Special Program Molecular Clinical Oncology “5 per mille”, University of Padua Strategic grant, IIT Excellence grant and Telethon to S.P.; AIRC PI and MIUR (Italian Minister of University) grants to S.D.

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Contributions

S.D., L.M. and S.P. designed research; L.M., S.D., M.A., E.E. and F.Z. performed experiments; M.C., S.B. and M.F. performed bioinformatics analysis; N.E. and S.G. prepared hydrogels; J.LeD. prepared micropost arrays; S.D. and S.P. coordinated the project; S.D. and S.P. wrote the manuscript.

Corresponding authors

Correspondence to Sirio Dupont or Stefano Piccolo.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Tables 1-3 and Supplementary Figures 1-33 with legends. (PDF 13818 kb)

Supplementary Tables

This file contains Supplementary Tables 4-6, which show the MAL/SRF and NF-kappaB signatures used in Supplementary Figure 2. (XLS 116 kb)

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Dupont, S., Morsut, L., Aragona, M. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011). https://doi.org/10.1038/nature10137

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