The Hippo senses force: a computational model of YAP/TAZ mechanosensing

BPJ_110_11.c1.inddDevelopment is driven by remarkably well-organized and deterministic processes, where molecular pathways and physical forces couple together to regulate cellular organization. One fundamental feature in development is the ability to stop growing when organs are fully formed. YAP/TAZ are remarkable molecules which have gained a great amount of attention due to their fundamental role in regulating organ size through the Hippo pathway, and more recently, through mechanical regulation. Given our lab’s long-term interest in studying cell behavior in response to extracellular environment, and the physical ECM properties in particular, we aim to get a better understanding of the mechanism for mechanosensing and its effect on YAP/TAZ regulation.

YAP/TAZ integrates  mechanosensing from both the ECM properties and the cell-cell interactions. Then how does YAP/TAZ, which shuttles from cytoplasm to the nucleus where they direct transcriptional programs, integrate signals from cell-ECM and cell-cell contacts? Furthermore, characterizing the integration of cell mechanics is challenging due to the difficulty in observing and quantifying mechanical properties and forces, as well as  the complexity of multiple pathways interacting in complicated dynamic manners. Therefore, computational models integrating signals from cell-ECM and cell-cell adhesion offer a promising approach to quantitatively understand YAP/TAZ regulation and downstream multicellular size control. Likewise, one can address the question why YAP/TAZ, but not other actin-regulated molecules such as SRF/MAL are the mechanical checkpoint of cells.

Cancer cells, which lose the precise mechanosensing of the environment always have upregulated YAP/TAZ to enhance survivals and proliferations. YAP/TAZ has also been found to be stemness relevant, such as regulating the differentiation directions. Thus having a general quantitative model can assist in understanding how mechanical sensing of biophysical properties regulates proliferation, survival, stem cell properties, or cancer malignancy. Our paper addresses these questions with a computational model, predicts the stiffness response of YAP/TAZ activity, and how this stiffness sensing is modified by inhibiting or overexpressing important regulators of the cytoskeleton. This model also allows us to investigate the synergy between canonical Hippo pathway and mechanical regulation of YAP/TAZ.

The cover image shows a configuration of cells which integrate signals from cell-cell interactions and the ECM to precisely control the shuttle of YAP/TAZ between cytoplasm and nucleus. YAP/TAZ, shown as small yellow molecules, diffuse around the cytoplasm. Their transport into the nucleus (dark red) is regulated quantitatively by an upstream signaling network (blue circuits). The violet region represents the partially unveiled environment that is filled with ECM, growth factors and others. The image was rendered using Adobe Photoshop software.

If you are more interested in our work, please check our website.

–       Meng Sun, Fabian Spill, Muhammad H. Zaman

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