Focal adhesion kinase - the reversible molecular mechanosensor

TL;DR

This paper investigates how focal adhesion kinase (FAK) functions as a reversible mechanosensor, responding to substrate stiffness and cellular forces, and elucidates the physical mechanisms behind its conformational changes.

Contribution

It provides a detailed physical model explaining the reversible mechanosensing mechanism of FAK and its dependence on mechanical cues from the environment.

Findings

FAK's conformational change rates depend on substrate stiffness and applied force.

The model aligns with observed cellular phenotypes on different substrates.

FAK acts as a reversible mechanosensor initiating chemical signals in response to mechanical stimuli.

Abstract

Sensors are the first element of the pathways that control the response of cells to their environment. After chemical, the next most important cue is mechanical, and protein complexes that produce or enable a chemical signal in response to a mechanical stimulus are called mechanosensors. There is a sharp distinction between sensing an external force or pressure/tension applied to the cell, and sensing the mechanical stiffness of the environment. We call the first mechanosensitivity of the 1st kind, and the latter mechanosensitivity of the 2nd kind. There are two variants of protein complexes that act as mechanosensors of the 2nd kind: producing either a one-off or a reversible action. The latent complex of TGF-$\beta$ is an example of the one-off action: on the release of active TGF-$\beta$ signal, the complex is discarded and needs to be replaced. In contrast, focal adhesion kinase (FAK) in a complex with integrin is a reversible mechanosensor, which initiates the chemical signal in its active phosphorylated conformation, but can spontaneously return to its closed folded conformation. Here we study the physical mechanism of the reversible mechanosensor of the 2nd kind, using FAK as a practical example. We find how the rates of conformation changes depend on the substrate stiffness and the pulling force applied from the cell cytoskeleton. The results compare well with the phenotype observations of cells on different substrates.