Molecular Mechanisms of Contractility-Based Cellular Mechanosensing

Mechanosensing is fundamental to numerous cellular functions, and myosin II is a core component of this mechanosensory machinery. Given the importance of successful cell division for maintaining genomic integrity, we reasoned that myosin II-mediated mechanosensing would be a significant factor in ensuring successful cytokinesis. We found that dividing cells are exquisitely sensitive to mechanical stress inputs, relocating myosin II to sites of the externally imposed stress. This system has the hallmark of a soft mechanical check-point, slowing cytokinesis until the deformation is corrected. The myosin II-based mechanosensing is performed by a three-part sensor, including force amplification through the myosin II lever arm, myosin bipolar thick filament (BTF) assembly, and actin filament anchoring by cortexillin I. Multi-scale modeling demonstrates how myosin II force-sensing and cooperative actin-binding couples to BTF assembly and quantitatively accounts for the amounts and kinetics of myosin mechanosensitive accumulation. Furthermore, forces are shared between myosin and different actin crosslinkers with myosin having potentiating or inhibitory effects on certain crosslinkers. Additionally, different types of cell deformations elicit distinct responses: myosin and α-actinin respond to dilation while filamin mainly reacts to shear. This myosin II-based mechanosensory system is part of a larger control system that tunes myosin accumulation at the cleavage furrow under diverse mechanical constraints. In this context, cortexillin I not only anchors the actin filaments, but also links to signal transduction proteins. These signaling proteins, including IQGAPs and the chromosomal passenger complex proteins, reinforce 'normal' signals that emanate from the mitotic spindle to direct myosin II accumulation. Overall, this control system demonstrates how mechanical inputs can be converted to signaling outputs in a manner analogous to chemical signal transduction.