BRIDGING THE GAP: A THEORETICAL MODEL OF
MECHANOTRANSDUCTION THROUGH ERK SIGNALLING
Johan Kerkhofs (1,2,3), Liesbet Geris (1,3), Bart Bosmans (2), Hans Van Oosterwyck(2,3)
1. Biomechanics Research Unit, U.Liège, Belgium; 2. Biomechanics section, K.U.Leuven, Belgium; 3. Prometheus Leuven R&D division of skeletal tissue
Introduction
Integrins play a crucial role in the mechanotransduction of anchorage-dependent cells. They transmit the mechanical signals and initiate signalling pathways which ultimately alters transcription in the cell nucleus. The dynamics of this process is poorly understood. We present a theoretical model that bridges the gap between mechanical signals and their regulation of intracellular signalling pathways. Specifically, we model the effect of integrin activation on the extracellular-signal regulated kinase (ERK) pathway and their interplay.
Methods
The model comprises an Ordinary Differential
Equations (ODE) model of the ERK signalling pathway (adapted from [Faratian, 2009]), coupled to a 1D rheological model of cell-matrix mechanics (adapted from [Moreo, 2007]) that considers extracellular matrix (ECM), integrin, cytoskeletal and nuclear (visco)elasticity and acto-myosin contractility. The ERK pathway is activated by stretching of integrin molecules. Integrin activation was made proportional to its
deformation. Several feedback
mechanisms between the intracellular and the mechanical model were implemented (Fig.1).
Results
The model predicted markedly different ERK activation for static versus dynamical loading (fig. 1). Figure 1: Coupling of cell mechanics to intracellular ERK model: A different response to static versus dynamic load arises from the interplay between the cell mechanical model and the intracellular ERK model. Furthermore, a sensitivity analysis among others demonstrated the importance of substrate stiffness for ERK signalling. Low substrate stiffness led to larger integrin deformation, thereby increasing the stimulation of the ERK pathway.
Discussion
The predicted ERK response to static versus dynamic loading qualitatively corresponded to the experimental results of [Fitzgerald, 2006]. In the model the differential response is the result of the interplay between repeated activation of the ERK phosphorylation pathway and the deactivation and recovery of the dephosphorylation pathway in synchrony with the force. At higher frequencies the dephosphorylation does not have enough time to recover. These results show the model’s potential in elucidating mechanotransduction phenomena. The sensitivity to an alteration in the ECM stiffness illustrates how the ECM stiffness influences
intracellular
signalling, which may give rise to different cell fates. The mechanical environment may have to be tailored to a specific cell fate, a finding which is e.g. important to tissue engineering and in fracture healing where the extracellular matrix becomes progressively stiffer.
Acknowledge
ments
Johan Kerkhofs is a PhD Fellow of the Research Foundation Flanders (FWO – Vlaanderen).References
Faratian et al, Cancer res, 69:6713-6720, 2009.
Fitzgerald et al, J Biol Chem, 34:24095-103, 2006. Moreo et al, Acta biomater, 4:613-621, 2007.