Spatiotemporal model of cellular mechanotransduction via Rho and YAP

TL;DR

This paper develops a spatiotemporal model of cellular mechanotransduction involving YAP and Rho, predicting YAP localization dynamics under various mechanical stimuli and feedback mechanisms.

Contribution

It introduces a novel framework integrating YAP and Rho interactions to explain cellular responses to mechanical forces, including oscillations and stimulus-dependent localization.

Findings

Model predicts stationary YAP ratios consistent with experiments.

Identifies potential oscillatory YAP localization due to feedback.

Shows YAP response follows cyclic mechanical stimuli.

Abstract

How cells sense and respond to mechanical stimuli remains an open question. Recent advances have identified the translocation of Yes-associated protein (YAP) between nucleus and cytoplasm as a central mechanism for sensing mechanical forces and regulating mechanotransduction. We formulate a spatiotemporal model of the mechanotransduction signalling pathway that includes coupling of YAP with the cell force-generation machinery through the Rho family of GTPases. Considering the active and inactive forms of a single Rho protein (GTP/GDP-bound) and of YAP (non-phosphorylated/phosphorylated), we study the cross-talk between cell polarization due to active Rho and YAP activation through its nuclear localization. For fixed mechanical stimuli, our model predicts stationary nuclear-to-cytoplasmic YAP ratios consistent with experimental data at varying adhesive cell area. We further predict damped and even sustained oscillations in the YAP nuclear-to-cytoplasmic ratio by accounting for recently reported positive and negative YAP-Rho feedback. Extending the framework to time-varying mechanical stimuli that simulate cyclic stretching and compression, we show that the YAP nuclear-to-cytoplasmic ratio's time dependence follows that of the cyclic mechanical stimulus. The model presents one of the first frameworks for understanding spatiotemporal YAP mechanotransduction, providing several predictions of possible YAP localization dynamics, and suggesting new directions for experimental and theoretical studies.