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BRIDGING THE GAP: A THEORETICAL MODEL OF MECHANOTRANSDUCTION THROUGH ERK SIGNALLING
Presentation 1148 − Topic 31. Mechanobiology and cell biomechanics
S419
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 engineering, K.U.Leuven, Belgium
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).
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.
Acknowledgements 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. Figure 1: Coupling of intracellular ERK model:
cell
mechanics
to
ESB2012: 18th Congress of the European Society of Biomechanics
Journal of Biomechanics 45(S1)
S419
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 engineering, K.U.Leuven, Belgium
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).
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.
Acknowledgements 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. Figure 1: Coupling of intracellular ERK model:
cell
mechanics
to
ESB2012: 18th Congress of the European Society of Biomechanics
Journal of Biomechanics 45(S1)