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All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System
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A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors
Mariaceleste Aragona1, Tito Panciera1, Andrea Manfrin1
1Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy.
Cell
|August 20, 2013
Summary
Tissue architecture and mechanical forces regulate cell proliferation via YAP/TAZ signaling. Physical cues like stretching and stiffness control cell growth, preventing diseases like cancer by maintaining spatial control.
Area of Science:
- Cell Biology
- Biophysics
- Developmental Biology
Background:
- Cellular decisions on proliferation or growth arrest are spatially regulated within tissues.
- Disruption of this spatial control is a key feature of diseases, notably cancer.
- The mechanisms establishing these spatial patterns remain incompletely understood.
Purpose of the Study:
- To investigate how physical and architectural features of multicellular sheets influence cellular proliferative capacity.
- To elucidate the role of mechanical regulation of YAP/TAZ (Yes-associated protein/T-and-zendrin) in controlling cell growth patterns.
Main Methods:
- Investigated the mechanical regulation of YAP/TAZ activity in response to physical cues in multicellular sheets.
- Identified key F-actin-binding proteins (Cofilin, CapZ, Gelsolin) involved in modulating YAP/TAZ activity.
- Examined the influence of mechanical stresses like stretching, curvature, and extracellular matrix stiffness.
Main Results:
- YAP/TAZ activity is restricted to cells experiencing mechanical stresses, such as stretching or residing at edges/curvatures of epithelial sheets.
- The stiffness of the extracellular matrix significantly impacts YAP/TAZ localization and activity.
- Cofilin, CapZ, and Gelsolin act as critical regulators, limiting YAP/TAZ activity under low mechanical stress conditions, including contact inhibition of proliferation.
Conclusions:
- Physical and architectural features of tissues mechanically regulate YAP/TAZ, thereby controlling cellular proliferation.
- Mechanical forces are identified as overarching regulators of YAP/TAZ in multicellular contexts.
- This mechanical regulation influences cellular responsiveness to Hippo, WNT, and GPCR signaling pathways.
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