Structurally governed cell mechanotransduction through multiscale modeling.
Mechanotransduction has been divided into mechanotransmission, mechanosensing, and mechanoresponse, although how a cell performs all three functions using the same set of structural components is still highly debated. Here, we bridge the gap between emerging molecular and systems-level understandings of mechanotransduction through a multiscale model linking these three phases. Our model incorporates a discrete network of actin filaments and associated proteins that responds to stretching through geometric relaxation. We assess three potential activating mechanisms at mechanosensitive crosslinks as inputs to a mixture model of molecular release and benchmark each using experimental data of mechanically-induced Rho GTPase FilGAP release from actin-filamin crosslinks. Our results suggest that filamin-FilGAP mechanotransduction response is best explained by a bandpass mechanism favoring release when crosslinking angles fall outside of a specific range. Our model further investigates the difference between ordered versus disordered networks and finds that a more disordered actin network may allow a cell to more finely tune control of molecular release enabling a more robust response.
Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
John
J
Kang
Dept. of Mechanical Engineering Technology, Point Park University, Pittsburgh, PA 15222, USA.
Kathleen M
KM
Puskar
Dept. of Bioengineering, McGill University, Montreal, Quebec H3A 0C3, Canada.
Allen J
AJ
Ehrlicher
1] Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA [2] Dept. of Mechanical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Philip R
PR
LeDuc
1] Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, PA 15213, USA [2] Dept. of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Russell S
RS
Schwartz
D008841:Actin Cytoskeleton / Q000502:physiology; D003198:Computer Simulation; D003598:Cytoskeletal Proteins / Q000502:physiology; D064448:Filamins / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000502:physiology; D040542:Mechanotransduction, Cellular; D008954:Models, Biological
D003598:Cytoskeletal Proteins; D064448:Filamins; D020690:GTPase-Activating Proteins