ARUP; ISBN: 978-0-9562121-5-3 - CMBBE 2012 - Cardiff University

The activation of integrins will depend on the mechanical stress in the focal adhesions.
Therefore a mechanical model of the cell is needed to estimate the response of the cell
and its components to an external force. The most important mechanical structure is the
cytoskeleton, which connects all the cell components and provides structural support. It
consists of microtubules, intermediate filaments and actin filaments. The actin
cytoskeleton is attached to the ECM via the integrins in the focal adhesions. The
mechanical model used in this work is based on the model of Moreo et al. [4]. To
explore additional influences the nucleus and a visco-elastic component for the
‘passive’ cytoskeleton (microtubules,
intermediate filaments) are added. The
model consists of linear elastic springs, a
dashpot and a force generating component
representing the actomyosin motors. The
relationship between strain and stress in
the force generating component is
parabolic, since there is an optimal
overlap between actin and myosin
filaments. The springs represent
intracellular components which can be
approximated as linear elastic: the nucleus,
the integrins in the focal adhesions and the
actin filaments. The passive cytoskeleton is
represented by a Maxwell viscoelastic
component, a spring and dashpot in series. The elastic component immediately responds
to mechanical stress by elongating, the dashpot dissipates the energy stored in the spring
over time, a phenomenon also known as stress relaxation. Finally the ECM is modelled
as a linear elastic component as well. The model is depicted in figure 2.
The ERK pathway is activated by stretching of the integrin molecules in the focal
adhesion complex (FAC). They can extend, unfold or dissociate. Unfolding and
dissociation can expose binding sites and thereby initiate the ERK pathway [7]. In the
model the number of active integrins linearly depends on the strain of the spring
representing the integrin molecules in the mechanical model. The parameter values to
characterize the model are taken from literature.
3.3 Feedback mechanisms
To model interactions between external
mechanical stimuli and intracellular
signaling through integrins we have
included several feedback mechanisms.
In one mechanism, activation of
integrin stimulates the formation of
focal adhesion through the focal
adhesion structural protein p130Cas [8].
Stretching p130Cas makes it more
susceptible to Src mediated
phosphorylation. Phosphorylated
p130Cas initiates the formation of more
focal adhesions and the recruitment of
Fig. 2 Mechanical model of a cell: the elasticity of integrin,
actin, the nucleus, the cytoskeleton and the ECM is
represented by a spring. The Dashpot represents the
viscosity of the cytoskeleton and the third type of
component represents the active force generating capacity
of actomyosin motors.
Fig. 3 Coupling of the cell mechanics to the intracellular
ERK model. The dynamic load has one a frequency of
0.053 Hz.
more integrins to strengthen the FAC [9]. This is incorporated in the model through a