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Mechanobiology of YAP and TAZ in physiology and disease

Nature Reviews Molecular Cell Biology volume 18, pages 758–770 (2017)Cite this article

Subjects

Key Points

  • Mechanical signals are fundamental regulators of cell behaviour, but how mechanical cues are sensed and transduced at the molecular level to regulate gene expression has long remained enigmatic.

  • YAP and TAZ have been identified as conserved mechanotransducers, reading a very diverse set of mechanical cues, from shear stress to cell shape and extracellular matrix rigidity, and translating them into cell-specific transcriptional programmes.

  • YAP and TAZ mechanotransduction offers new means to interpret and study classic aspects of tissue physiology and pathology in molecular terms.

  • YAP and TAZ as mechanotransducers provide insight into how aberrant cell mechanics drive the onset of multiple diseases, including atherosclerosis, fibrosis, cardiac hypertrophy, muscular dystrophy and cancer.

Abstract

A growing body of evidence suggests that mechanical signals emanating from the cell's microenvironment are fundamental regulators of cell behaviour. Moreover, at the macroscopic scale, the influence of forces, such as the forces generated by blood flow, muscle contraction, gravity and overall tissue rigidity (for example, inside of a tumour lump), is central to our understanding of physiology and disease pathogenesis. Still, how mechanical cues are sensed and transduced at the molecular level to regulate gene expression has long remained enigmatic. The identification of the transcription factors YAP and TAZ as mechanotransducers started to fill this gap. YAP and TAZ read a broad range of mechanical cues, from shear stress to cell shape and extracellular matrix rigidity, and translate them into cell-specific transcriptional programmes. YAP and TAZ mechanotransduction is critical for driving stem cell behaviour and regeneration, and it sheds new light on the mechanisms by which aberrant cell mechanics is instrumental for the onset of multiple diseases, such as atherosclerosis, fibrosis, pulmonary hypertension, inflammation, muscular dystrophy and cancer.

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Figure 1: Schematic representations of mechanical stimuli influencing YAP and TAZ subcellular localization and activity.
Figure 2: Biological responses caused by nuclear accumulation and activation of YAP and TAZ by high levels of mechanical signalling.
Figure 3: Biological responses caused by cytoplasmic YAP and TAZ retention and inhibition due to low levels of mechanical stimuli.
Figure 4: Molecular players involved in YAP and TAZ mechanotransduction.
Figure 5: YAP and TAZ mechanotransduction in stem cell biology.
Figure 6: Deregulation of YAP and TAZ mechanotransduction in disease.

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Acknowledgements

The authors thank all members of the S.P. laboratory for discussion. This work is supported by AIRC Special Program Molecular Clinical Oncology '5 per mille', by an AIRC PI-Grant to S.P., and by Epigenetics Flagship project CNR-MIUR grants to S.P. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 670126-DENOVOSTEM).

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Authors and Affiliations

  1. Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, Padua, 35126, Italy

    Tito Panciera, Luca Azzolin, Michelangelo Cordenonsi & Stefano Piccolo

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  1. Tito Panciera
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  2. Luca Azzolin
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  3. Michelangelo Cordenonsi
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  4. Stefano Piccolo
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All authors contributed equally to all aspects of the article (researching data for article, substantial contribution to discussion of content, writing, review/editing of manuscript before submission).

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Correspondence to Stefano Piccolo.

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PowerPoint slides

Glossary

Shear stress

The force vector component coplanar with a material cross section; a fluid moving along a solid boundary will generate a shear stress on that boundary.

TEAD factors

(TEA domain family members; also known as TEFs). A family of DNA-binding transcription factors that cannot induce target gene transcription on their own but need to associate with specific cofactors, such as YAP and TAZ.

Mechanotransduction

Mechanisms by which cells convert mechanical signals conveyed by the microenvironment into biochemical signals to adapt their behaviour to the environment.

Capping proteins

Proteins (including CapZ but also ADF/cofilin, which are also F-actin-severing proteins) that bind to the growing (barbed) end of F-actin filaments, blocking the binding of other actin subunits to the growing filament.

Vinculin

A focal adhesion protein that links the cytosolic domain of integrins to the F-actin cytoskeleton.

Talins

Focal adhesion proteins that link integrin to the F-actin cytoskeleton either directly or indirectly (through binding to vinculin or α-actinin).

Focal adhesion kinase

(FAK). A cytosolic tyrosine kinase associated with focal adhesions and required for integrin-dependent cell motility, cell spreading and cell survival.

SRC-family kinases

A family of tyrosine kinases (composed of nine different members: SRC, YES, FYN, FGR, LCK, HCK, BLK, LYN and FRK) that can target cytosolic, nuclear or membrane proteins, having a broad impact on the phosphotyrosine proteome and on diverse cell behaviours.

RHO-associated protein kinase

(ROCK). A serine/threonine kinase that is best understood as a downstream effector of the small GTPase RHOA. ROCK favours formation of stress fibres and contractility of the actomyosin cytoskeleton by phosphorylating LIM domain kinase and myosin light chain kinase.

Intestinal crypts

Simple tubular invaginations at the base of intestinal villi (also known as crypts of Lieberkühn). Intestinal crypts are lined by various cell types: goblet, enteroendocrine, tuft, Paneth cells and intestinal stem cells.

Trophoblast

The outer layer of a blastocyst, composed of polarized cells from which part of the placenta originates.

Inner cell mass

(ICM). A mass of cells lying on one side of the blastocyst cavity from which all the adult tissues eventually derive.

Blastocyst

A structure formed during the development of mammalian embryos after the morula stage and before implantation, and is composed of an external layer (trophoblast) surrounding an internal cavity (blastocoel) and the inner cell mass.

Elastic modulus

A measure of the resistance of an object to elastic deformation.

Enamel

One of the four different tissues that compose the tooth; it is the outermost, highly mineralized tissue formed by epithelial cells known as ameloblasts.

LIM domain kinase

An actin-bound kinase that phosphorylates and inactivates actin-binding and actin-severing proteins, such as ADF/cofilin, thereby fostering the stabilization of F-actin filaments. LIM domain kinases are activated by RHO GTPases.

Foam cells

Lipid-filled M2 macrophages that form when monocytes are recruited to an atherogenic area of the arterial wall and contribute to the formation of the atherosclerotic plaque; these cells are derived from monocytes that engulf lipoprotein particles.

Vessel stenosis

Abnormal narrowing of a blood vessel (might be referred to as coarctation in the case of the carotid artery).

Coronary angioplasty

A surgical endovascular procedure performed to widen the narrowed (stenotic) coronary arteries of the heart.

Adventitial fibroblasts

Fibroblasts that are part of the area between the external elastic lamina and the outermost edge of a blood vessel (adventitia).

Lysyl oxidase

(LOX). An enzyme that promotes collagen and elastin crosslinking.

Hepatic stellate cells

Pericytes found in the perisinusoidal space of the liver; these are the major cell type involved in fibrosis in response to liver damage.

Metaplasia

Reversible transition of a differentiated cell type to another differentiated cell type that can be caused in a tissue by an abnormal stimulus; once the stimulus ceases, the tissue returns to its normal differentiation condition. Metaplasia is often considered an early phase of the tumorigenic process.

Myoblasts

Embryonic progenitor cells that can differentiate into muscle cells. Myoblasts that do not differentiate into muscle cells in the skeletal muscle fibre can turn into satellite cells (somatic muscle stem cells).

Linker of nucleoskeleton and cytoskeleton (LINC) complex

A protein complex associated with the nuclear membrane and composed of SUN domain and KASH domain proteins. This complex serves as a linker connecting nuclear lamins and chromatin with cytosolic actin microfilaments, microtubule filaments and intermediate filaments.

Evo-devo

(evolutionary developmental biology). A field in biological studies that compares the developmental processes of different organisms to trace their evolutionary relationships and to infer the evolution of developmental processes.

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Panciera, T., Azzolin, L., Cordenonsi, M. et al. Mechanobiology of YAP and TAZ in physiology and disease. Nat Rev Mol Cell Biol 18, 758–770 (2017). https://doi.org/10.1038/nrm.2017.87

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