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Cell junctions with the ECM: A mechanical Basis of memory?
On Wednesday we provided an overview of adhesions cells are making to each other and
the ECM. In that we spoke about different parts and types of adhesions, including their
different roles and generalised structures that bind to proteins.
Today we are going to discuss mechanical computation in cells and identify how adhesion
cites are used as signaling centers.
Reading: 9th edition, Molecular Cell Biology.
Binary switch domains and biomechanical sense of adhesion.
Mechanobiology: this is the idea that there is a physical component to how cells bond and
behave.
Mechano transduction: the idea that the cell can feel the environment and generate the
biological response.
Every cell is connected via the ECM, sending mechanical signals which create cell
response. Textbook view shows the integrins binding to ECM, coupled by kindlin.
These attachments, contribute to every process in our body. The cells read these signals
and respond appropriately.
Adhesion of animal cells to the ECM is important in:
Cell proliferation
Suppression if apoptosis
Regulation of gene expression – if we look at this, we can see it differentiate into
different cell types.
Wound healing
Cell migration
Experiment to test the adhesion of cells to the ECM:
Take a population of stem cells à these are differentiated into adipocyte, neuron, myocyte,
and osteocyte.
This one population of stem cells is in all types of media, if you put these cells onto a slide
with different substrate stiffness (i.e. glass, gel etc..) The cell identifies the physicality of the
environment and reprograms accordingly.
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, The cells cytoplasmic tails have Talin pulling on it to try and work out what to do. The pulling
forces and ECM forces lead to the reprogramming of the cell. The sensors in Talin are
getting stretched and recruit signals to the site to instruct the cell how to behave. Vinculin
comes in and attaches GTP to Talin.
Diverse structures mediated by Integrin: Talin: Actin
à Fruit fly
à cell undergoing mitosis.
à Cell migration
à Podosomes
à Synaptic adhesions – if you knock out Integrin or Talin the synapses are unable to
communicate.
Domain structure of Talin
Activate integrin binds to the membrane, agonist stimulation triggers a signaling membrane
targeting Talin. Talins bind the integrin Beta tail causing the separation of the two tails of
intergrin subunits, relieving the constraint and activating integrin. During cell spreading, the
active region is stretched, and vinculin binds due to the forces on the rearward moving actin
filaments. This converts ECM forces to biochemical signals, organising and stabilising the
links, signalling transduction events through the integrins, vinculin and actin.
The Talin R3 domain acts as a binary switche, existing in two different states folded or
extended.
1. In the folded state it binds to one set of molecules i.e. RIAM.
2. In the open state it exposes vinculin binding sites. These are switches, which
enhance the strength and force drives a change in biological signaling.
R3 bound to effective RIAM
When you pull the weakest domain it unfolds, destroys the binding site for one vinculin and
opens two new binding sites for other vinculins. Stretching Talin activates vinculin. The
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