Principles of Cell communiction Flashcards
What is cell signalling?
- Cells in multicellular organisms must
communicate with each other in
order to organise themselves into a
functioning unit - Cells sending signals must be able to
control the signals they are sending,
and receiving cells must be able to
interpret the information accurately - Communication is often mediated by
extracellular signaling molecules - Signaling molecules must then bind
to cell receptors, and the signal
transduced within the cell - Effector molecules then alter the
behaviour of the cell accordingly
How are messages relayed and give examples?
Using signalling molecules
- Nucleotides
- Small molecules
- Steroids
- Proteins and peptides
- Fatty acids
- Dissolved gases
What distances can extracellular signals act over?
Short or long
What is the first way of getting a signal to the right place?
– (i) Contact-Dependent
– Especially important in development
and immune response
– Also involved widely in determining
cell fate, (e.g. nerve cells and gut
lining
What is the second way?
– (ii) Paracrine
– Cells release signalling molecules
into the extracellular fluid
– Paracrine signalling acts locally on
neighbouring cells
– Rapidly taken up and sequestered or
destroyed by recipient cells, so signal
does not diffuse far
Third method
– (iii) Synaptic
– secretion of a chemical signal across
a space as a result of an electrical
impulse
– Short range (from the perspective of
cell-cell contact)
– Long range (due to the length of the
cell)
– Very fast, very specific
– High concentrations, low affinities
Fourth method?
– (iv) Endocrine
– long range signaling to cells that
might lie anywhere in the body
– Signals (hormones) secreted into the
blood stream
– Gets diluted many millions of times,
so needs to act at very low
concentrations
Fifth way?
– (v) Gap junctions
– Direct communication between
neighbouring cells
– Narrow, cytoplasmic filled channels
– Allows exchange of inorganic ions
and other small molecules (e.g.
Ca2+, cAMP)
– As not all neighbouring cells have
them, allows directionality of signal
Where do extracelular signals need to be communicated?
Inside the cell
How can extracellular signals be communicated inside the cell?
– Directly. The signal itself passes in to
the cell (steroids, gap junctions)
– Indirectly. The signal binds a cell
surface receptor to induce a
conformational change
What are the three clases that exist?
- Ion-channel coupled
– involved in rapid synaptic
signaling and in muscle cells
– Gated channels which undergo a
conformational twist upon ligand
binding
– Removes charged residues from
the channel, allowing influx of
ions - G-protein coupled
– Receptors have 7 TM domains
(serpentine)
– Upon ligand binding, change
shape to bind trimeric G
proteins (alpha, beta, gamma subunits) - Enzyme-coupled receptors
– TM proteins (usually 1 TM
domain)
– Either are an enzyme or directly
bind one
– Most common are Receptor
Tyrosine kinases
– Autophosphorylation causes
docking sites for downstream
effectors
How are signals transduced?
By reversible signals causing 3D conformational changes
Describe modulation of signals by molecular switches
- Most phosphorylation occurs at either
serine or threonine amino acids of the
substrate protein. - Each protein phosphorylation leads to a
shape change due to the interaction
between the phosphate group and charged
or polar amino acids. - Each protein kinase is antagonised by a
protein phosphatase, allowing rapid reversal
of the signal - Many substrates are themselves kinases,
leading to “cascades”
What is the other type of switch?
- Other type of switch is the small
monomeric GTPase - Conformational change upon exchange
of GDP for GTP allows them to bind
target proteins - Regulated by GAPs, GEFs and GDIs
- GTPases can be modulated by
phosphorylation
How do protein-protein interactions occur?
Through modular interaction domains
Describe protein-protein interactions through modular interaction domains
- Bringing signaling proteins into close
proximity is sometimes sufficient to
allow strong interactions to form - Matches interaction domains with
targets:
– Short peptide sequences
– Phosphate groups
– Other protein domains - Dynamic process of many small “flexes”,
to find the right fit
How do signalling proteins work together?
As multi-protein complexes
* One intracellular signal results in the functional modification (activation/inactivation/
relocalisation) of many proteins
* It makes sense to spatially couple some of these downstream pathways. Can be:
– pre-formed but inactive, prior to signal
– formed only upon activation by signal
How can signals be amplified?
- Multiple steps between extracellular
ligand binding and activation of
effector proteins allow amplification
of signal:
– e.g. 1 molecule of active receptor
could activate 10 molecules of G
protein/sec
– Leads to activation of 10 molecules
of kinase/sec
– Which phosphorylates 10 molecules
of kinase/sec
– Which phosphorylates 10 metabolic
enzymes/sec
– Which equates to a x10,000
activation response
Consequence: very small changes in initial conditions can lead to very large responses
How can signals be modulated?
- Cells can respond to signals with a gradual, or an
“all or nothing” response - Most responses appear to fall somewhere in
between – and is cell-specific - Allostery – where more than one signaling
molecule must bind its target to produce a
response – can produce “switch”-like behaviour - True switches use feedback mechanisms
Describe positive feedback
- In positive feedback, the output stimulates its
own production:
An upstream kinase (S), activates the effector kinase
(E), which phosphorylates a number of targets to
produce a response
A constantly active phosphatase (I), inactivates E - If there is no feedback pathway, subsequent loss of S
will lead to inactivation of E by I, and a loss of
response. - In positive feedback, E additionally phosphorylates and
activates itself - Turning off the signal (S) at source now has no effect
on the activation of kinase E
This type of signal is prevalent during development,
when cells are sent down specific fates
Describe negative feedback
- In negative feedback, the output inhibits its
own production: - E phosphorylates and activates the phosphatase (I),
increasing the rate of its own dephosphorylation - If there is only a short delay between signal and
phosphatase activation, there will be an initial high
response, followed by an attenuation, even though
the signal remains - If there is a long delay, the activity of the kinase drops
below a threshold, inactivating the phosphatase - Continued signal will lead to a further burst of kinase
activation (which again leads to phosphatase
activation) - Continues to oscillate until the signal is removed
This type of signal is seen during rhythmical cycles
Describe integrated signals
- One signal can regulate many different
signal transduction pathways - Typically, a single cell will simultaneously see
many signaling molecules - Without feedback and control, the response
would be chaotic - Signaling pathways co-ordinate with each
other to produce an appropriate cellular
response - Understanding how such a complex system
of interactions can lead to co-ordinated
emergent behaviour is one of the goals of
Systems Biology
Describe signal speed
- Signal speed depends on the way in
which a cell receives the signal - Binding of a neurotransmitter to an ion
channel, or phosphorylation of a protein
takes milliseconds - If all appropriate proteins are already in
the cell, the response can be rapid:
– Secretion
– Metabolism
– Cell movement - When the response involves gene
expression, it can take hours or days:
– Cell growth and division
– Cell differentiation
Does input equate to output?
No
- Most cells require signals just to stay alive
- Other combinations of signals cause cell growth or
differentiation - Even when the same signals are present, two cells
may respond differently:
– Individual cells have varying levels of particular
proteins
– the absolute combination of signals seen by a single
cell at a single point in time will vary
