Spatiotemporal model of cellular mechanotransduction via Rho and YAP

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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.

Original languageEnglish
JournalIntegrative Biology
Volume13
Issue number8
Pages (from-to)197-209
Number of pages13
ISSN1757-9694
DOIs
Publication statusPublished - 17 Aug 2021

    Research areas

  • YAP activation, Rho GTPase signalling, YAP nuclear translocation, cell polarization, mechanotransduction, protein oscillations, HIPPO PATHWAY, NUCLEAR-LOCALIZATION, YAP/TAZ ACTIVITY, MECHANICAL CUES, DYNAMICS, POLARITY, GROWTH, TAZ, MECHANOBIOLOGY, PHYSIOLOGY

ID: 291115785