Mechanotransduction:

how do cells sense and respond

to mechanical events?
 Mechanotransduction
In living cells, application of a mechanical stimulus
causes not only a mechanical response but also a
biological response.

Using complex networks of sensors, transducers and

actuating mechanisms, cells are able to respond and
adapt to their mechanical environment

These effects can be profound and critical to normal

physiology and, in some cases, pathology.

It is useful to consider what components a cell needs

to respond to a mechanical stimulus.
 components
Mechanoreception.
First, a cell must detect the stimulus and relay the message from
outside the cell (where the stimulus acts) to inside the cell (where a
response will ultimately be generated). To do so, cells use
mechanoreceptors.

Signal transmission.
Once sensed, the mechanical signal then needs to be relayed within
the cell to various targets throughout the cell; cells appear to use
both biochemical pathways and the cytoskeleton to transmit this
signal.

Target activation.
When the signal reaches its target (usually a protein), the target is
activated. This causes alterations in cell behaviour through a variety
of molecular mechanisms.
 Mechanoreceptors
Since mechanoreceptors must respond to
extracellular signals and relay the signals from
outside the cell to inside the cell, it makes sense that
mechanoreceptors are physically located in the
plasma membrane, at the junction of extracellular
and intracellular spaces

Several mechanoreceptors have been identified in

this location
Integrins
Stretch-activated ion channels
Cell-surface receptor proteins
Candidate mechanoreceptors for relaying extracellular mechanical signals to the cells
interior to activate intracellular signaling pathways. Connections between receptors probably
exist; for example, forces received by integrins cause deformation of the cytoskeleton (dark
blue line), which tugs on the ion channel (as indicated by the red dotted arrow), causing
the channel to open permitting flow of ions.
 Integrins
Integrins are transmembrane proteins that link the ECM to
the cytoskeleton via focal adhesion proteins in the cytoplasm.
Because of the physical connection between the ECM and
cytosolic components, a mechanical stimulus applied to
integrins can alter the structure of the cytoskeleton directly.
Deformation of the cytoskeleton can have numerous
consequences:

The physical properties of the cell will change, as predicted

by the analytical models
Other receptors in the cell, including ion channels and other
cell-surface receptors, can be activated
Biochemical and molecular events within the cell may be
regulated directly
 Stretch-activated ion channels
Ion channels are proteins that span the plasma membrane,
connecting the cytosol to the cell exterior.

Ion channels are highly selective, allowing diffusion of specific

inorganic ions across the lipid bilayer

These ions, which include Na+, K+, Ca2+,and Cl, are involved in a
multitude of cellular activities, including intracellular signaling,
gene expression, transcription, translation, and protein synthesis.

They are not always open instead they are gated, meaning a
specific stimulus can cause them to open briefly, thereby allowing
the flow of ions either into or out of the cell depending on the
electrochemical gradients.
 Opening of ion channels typically involves
an alteration in the channels physical
configuration.

The cytoplasmic extensions of stretch-

activated ion channels are attached to the
cytoskeleton, and therefore deformation of
the actin cytoskeleton can regulate gating
of the channel.
 Cell-surface receptor proteins
In order to respond to cues from their environment,
cells rely on cell-surface receptors that bind signaling
molecules to initiate an intracellular response

These cell-surface receptors are broadly classified as

either G protein-linked or enzyme linked

Typically, receptors respond to soluble extracellular

signal molecules, such as proteins, small peptides,
steroids, or dissolved gases, also to mechanical
signals
 The conformation of cell-surface receptors may be
altered by membrane deformation, switching them
from an inactive to an active state.

Additionally, the cytoskeleton and focal adhesions may

play roles in activation of these receptors. For instance,
subunits of G proteins have been shown to be localized
to sites of focal adhesions, in close proximity to
integrins and the cytoskeleton

When G protein-linked and enzyme-linked receptors

are activated, they initiate several intracellular
signaling pathways that distribute the signal
throughout the cell, ultimately altering its behaviour.
 Intracellular signal transduction
Once a mechanical stimulus is sensed and
transferred from outside the cell, the signal
needs to be transmitted to other points within
the cell where a molecular response can be
generated.

It appears that cells rely on both physical and

biochemical mechanisms to transmit
mechanical signals
Cytoskeleton-mediated signal transduction

Transmission of mechanical signals via integrins can

lead to deformation of the cytoskeleton, which, in
turn, can affect the biochemical state of the cell.

1. Decentralization mechanism
The cytoskeleton is a continuous, dynamic network
that provides mechanical connections between
intracellular structures, deformation of the
cytoskeleton at one location may lead to
deformations of connected structures at remote
locations
2. Activation of regulatory molecules immobilized on the
cytoskeleton
It has been proposed that these regulatory molecules
will experience the mechanical load imposed on the
cytoskeleton as a consequence of their binding to it.

The imposed load could alter the conformation of the

regulatory molecules, which, in turn, would change
their kinetic behaviour and biochemical activity

Thus, the cytoskeleton and its associated regulatory

molecules might serve as a scaffold for the
transduction of mechanical signals to biochemical
signals within the cell.
 Biochemically mediated signal transduction

The general principle behind biochemically mediated

signal transduction is that activation of a receptor
initiates a cascade of events mediated by a series of
signaling molecules like second messengers

Ultimately these molecules interact with target

proteins, altering the target proteins so they elicit
changes in the behaviour of the cell.
Schematic of simple intracellular signalling pathways
using biochemical mediators.
 Interestingly, in addition to their mechanical
transmission role, integrins are also able to induce
biochemical responses.

For instance, clustering of integrins at focal adhesion

sites leads to recruitment and activation of signaling
molecules (e.g.,focal adhesion kinase or FAK),
thereby initiating biochemical signal transduction

Ultimately, the biochemical signaling pathways

interact with target proteins, which are responsible
for altering the behavior of the cell.
 Cellular response to mechanical signals
Mechanical signals, like other extracellular signals, can
influence cellular function at multiple levels,
depending on the targets of the signaling pathways
initiated by the stimulus

For instance, a signaling pathway activated by a

mechanical stimulus might target proteins that
regulate gene expression and the transcription of
mRNA from DNA (e.g., transcription factors).

Additionally, the signaling targets might be molecules

involved in protein production, so that alteration of
those molecules will affect translation of mRNA to
proteins or posttranscriptional assembly or secretion of
proteins.
 Because cell shape and motility are dependent on the
cytoskeleton, its deformation by a mechanical stimulus
can alter these cytoskeleton-dependent processes.

production of proteins and their secretion from a cell

can affect the function of neighboring cells (or even the
secreting cell itself), thereby propagating the effect of
the mechanical signal from one cell to several.

It is important to realize that the cellular response to a

single type of stimulus can be quite complex, since
activation of a single type of receptor usually activates
multiple parallel signaling pathways and therefore can
influence multiple aspects of cell behavior.
 Furthermore, at any one time, cells are receiving
hundreds of different signals from their environment
and their response is determined by integration of all
the information they receive.

Clearly, this makes things rather complicated,

particularly if one wants to understand the response
of a cell to a particular mechanical stimulus.

Efforts to understand the response of cells to

mechanical stimuli often rely on experiments
performed under controlled conditions in the
laboratory.
Modelling actin filaments as a foam
 Relative density

Deformation
Shear stress- F/l2
Shear strain - /l
Shear modulus-

Relative modulus