A Kinematic Model Coupling Cytoskeletal Dynamics with JNK Activation in Response to Matrix Stretching

The role of the actin cytoskeleton in regulating mechanotransduction in response to external forces is complex and incompletely understood. Here, we develop a mathematical model coupling the dynamic disassembly and reassembly of actin stress fibers and associated focal adhesions to the activation of cjun Nterminal kinase (JNK) in cells attached to deformable matrices. The model is based on the assumptions that stress fibers are preextended at a "homeostatic" level under normal, nonperturbed conditions, and that perturbations in stress fiber length destabilize stress fibers. The subsequent reassembly of fibers upregulates the rate of JNK phosphorylation as a result of the formation of new integrin bonds within the associated focal adhesions, while the rate of JNK dephosphorylation is independent of the stretch signal. Disassembly of overly stretched stress fibers and reassembly of stress fibers at the "homeostatic" level lead to a decrease in the rates of integrin turnover and JNK activation. Numerical solutions of the model equations predict that different patterns of matrix stretch result in distinct temporal patterns in JNK activation that compare well with published experimental results. This model describes a mechanism by which the dynamic properties of the actin cytoskeleton allow cells to adapt to applied forces to modulate intracellular signaling.

A Kinematic Model Coupling Cytoskeletal Dynamics with JNK Activation in Response to Matrix Stretching Academic Article