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Mechanobiology of YAP and TAZ in physiology and disease.

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.

SUBMITTER: Panciera T

PROVIDER: S-EPMC6192510 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Mechanobiology of YAP and TAZ in physiology and disease.

Panciera Tito T Azzolin Luca L Cordenonsi Michelangelo M Piccolo Stefano S

Nature reviews. Molecular cell biology 20170927 12

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 ...[more]

PMID: 28951564

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Project description:In cell proliferation, stem cell differentiation, chemoresistance, and tissue organization, the ubiquitous role of YAP/TAZ continues to impact our fundamental understanding in numerous physiological and disease systems. YAP/TAZ is an important signaling nexus integrating diverse mechanical and biochemical signals, such as ECM stiffness, adhesion ligand density, or cell-cell contacts, and thus strongly influences cell fate. Recent studies show that YAP/TAZ mechanical sensing is dependent on RhoA-regulated stress fibers. However, current understanding of YAP/TAZ remains limited due to the unknown interaction between the canonical Hippo pathway and cell tension. Furthermore, the multiscale relationship connecting adhesion signaling to YAP/TAZ activity through cytoskeleton dynamics remains poorly understood. To identify the roles of key signaling molecules in mechanical signal sensing and transduction, we present a, to our knowledge, novel computational model of the YAP/TAZ signaling pathway. This model converts extracellular-matrix mechanical properties to biochemical signals via adhesion, and integrates intracellular signaling cascades associated with cytoskeleton dynamics. We perform perturbations of molecular levels and sensitivity analyses to predict how various signaling molecules affect YAP/TAZ activity. Adhesion molecules, such as FAK, are predicted to rescue YAP/TAZ activity in soft environments via the RhoA pathway. We also found that changes of molecule concentrations result in different patterns of YAP/TAZ stiffness response. We also investigate the sensitivity of YAP/TAZ activity to ECM stiffness, and compare with that of SRF/MAL, which is another important regulator of differentiation. In addition, the model shows that the unresolved synergistic effect of YAP/TAZ activity between the mechanosensing and the Hippo pathways can be explained by the interaction of LIM-kinase and LATS. Overall, our model provides a, to our knowledge, novel platform for studying YAP/TAZ activity in the context of integrating different signaling pathways. This platform can be used to gain, to our knowledge, new fundamental insights into roles of key molecular and mechanical regulators on development, tissue engineering, or tumor progression.

Project description:Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8?kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-? as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-?-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.

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Mechanobiology of YAP and TAZ in physiology and disease.

Publications

Mechanobiology of YAP and TAZ in physiology and disease.

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