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Cooperative mechanosensitivity and allostery of focal adhesion clusters

Accepted version
Peer-reviewed

Type

Article

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Authors

Foo, DCW 
Terentjev, EM 

Abstract

We analyse a role of cooperative interaction between neighbouring adhesion-mechanosensor complexes by constructing an Ising-like Hamiltonian describing the free energy of cell adhesion on a substrate as a lattice of 3-state mechanosensing sites involving focal adhesion kinase (FAK). We use Monte Carlo stochastic algorithm to find equilibrium configurations of these mechanosensors in two representative geometries: on a 1D ring representing the rim of a cell on at surface, and a 2D bounded surface representing the whole area of cell contact with flat surface. The level of FAK activation depend on the pulling force applied to the individual FAK-integrin via actin-myosin contractile networks, and the details of the coupling between individual sensors in a cluster. Strong coupling is shown to make the FAK sensors experience a sharp on-o behaviour in their activation, while at low coupling the activation/autoinhibition transition occurs over a broad range of pulling force. We fi nd that the activation/autoinhibition transition of FAK in the 2D system with strong coupling occurs with a hysteresis, the width of which depends on the rate of change of force. The effect of introducing a regulating protein (such as Src) in limited quantity to control FAK activation is explored, and visualizations of clustering in both topologies are presented. In particular the results on the bounded 2D surface indicate that clustering of active FAK occurs preferentially at the boundary, in agreement with experimental observations of focal adhesions in cells.

Description

Keywords

Cell Adhesion, Focal Adhesions, Mechanotransduction, Cellular, Models, Molecular, Monte Carlo Method, Phosphorylation, Stochastic Processes

Journal Title

Physical Biology

Conference Name

Journal ISSN

1478-3967
1478-3975

Volume Title

Publisher

IOP Publishing
Sponsorship
Engineering and Physical Sciences Research Council (EP/F032773/1)
This work has been funded by UROP scheme by the Department of Physics, University of Cambridge.