Spatiotemporal model of cellular mechanotransduction via Rho and YAP
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Spatiotemporal model of cellular mechanotransduction via Rho and YAP. / Novev, Javor Kirilov; Heltberg, Mathias L.; Jensen, Mogens H.; Doostmohammadi, Amin.
In: Integrative Biology, Vol. 13, No. 8, 17.08.2021, p. 197-209.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Spatiotemporal model of cellular mechanotransduction via Rho and YAP
AU - Novev, Javor Kirilov
AU - Heltberg, Mathias L.
AU - Jensen, Mogens H.
AU - Doostmohammadi, Amin
PY - 2021/8/17
Y1 - 2021/8/17
N2 - 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.
AB - 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.
KW - YAP activation
KW - Rho GTPase signalling
KW - YAP nuclear translocation
KW - cell polarization
KW - mechanotransduction
KW - protein oscillations
KW - HIPPO PATHWAY
KW - NUCLEAR-LOCALIZATION
KW - YAP/TAZ ACTIVITY
KW - MECHANICAL CUES
KW - DYNAMICS
KW - POLARITY
KW - GROWTH
KW - TAZ
KW - MECHANOBIOLOGY
KW - PHYSIOLOGY
U2 - 10.1093/intbio/zyab012
DO - 10.1093/intbio/zyab012
M3 - Journal article
C2 - 34278428
VL - 13
SP - 197
EP - 209
JO - Integrative Biology (United Kingdom)
JF - Integrative Biology (United Kingdom)
SN - 1757-9694
IS - 8
ER -
ID: 291115785