Dynamic Cell
Cell Signalling – Basic Concept
Usually involves a receptor molecule that recognises the signal in a highly specific manner. Allows the
receiving cell to make a characteristic response.
• Chemical signal released by one cell
• Recognised by another cell – this can be on cell surfaces or within the cells
Why is cell signalling important? (communication)
• Essential for co-ordination of cell behaviour
Single cell organisms, such as yeast, use signalling to identify and interact with cells of the correct mating
type in sexual reproduction. Multicellular organisms depend on cell signalling for correct development,
tissue maintenance and homeostasis.
Cell communication in a nutshell
Essential link between extracellular stimulus and control of:
• Metabolism
• Proliferation
• Movement
How does cell communication occur?
• Intercellular messenger secretion – between cells
• Message reception
• Intracellular signalling/signal transduction/signal processing –
inside the cell
• Cellular response
Signal-receptor interaction starts a chain of molecular changes within the cell
Signals received by a cell surface receptor are typically relayed through the cell by a
series of molecular interactions that result in changes, both in the cytoplasm (e.g.
altered metabolism or cytoskeleton) and nucleus (altered gene expression).
The molecular relay can allow:
• modulation of the signalling pathway, for instance cross-talk with other signalling
pathways;
• amplification of the pathway.
Why do we care about cell communication?
• All living cells recognize signals from the environment; absolutely essential for the survival of
multicellular organisms.
• Vast majority of drugs target signaling proteins. Half of all drugs target G-protein coupled receptors,
Kinases are currently most studied class of drug target.
• Impossible to understand cell biology without understanding how information transfer happens in cells
-> central to understanding all known physiological processes - particularly important in biomedical
science.
Ancestral mechanisms of cell communication in unicellular organisms
• Quorum sensing in bacteria.
• Chemotaxis in Dictostylium amoebae.
• Mating response in budding yeast (Saccharomyces cervisiae).
,Receptors usually associate with signalling ligands at the cell surface
intercellular
Ligand-receptor interactions mediate communication between cells
• Universal feature -> molecule is secreted by one cell and binds to a receptor on another cell. Most
signalling molecules are hydrophilic -> easily transported in blood and other aqueous fluids -> act on
extracellular receptor domains.
• Hydrophobic exceptions -> transported through the bloodstream by carrier proteins -> act on
intracellular receptors.
Intercellular signalling can happen over long or short distances using four major mechanisms
Signalling molecules can be:
• Amino acids • Nucleotides
• Peptides • Fatty acids
• Proteins • Steroids
• Gases like NO or CO
Multicellular organisms use 100s of different kinds of molecule to communicate (amino acids, gases
peptides etc…). Four major types of intercellular signalling:
1. Contact dependent/juxtacrine - tethered ligand causes
response in adjacent cells. E.g delta
2. Paracrine (and autocrine) - secreted ligand acts in a highly
localised manner-molecule diffusion limited. E.g Nitric oxide
3. Synaptic- long structures (axons) connect transmitter cells to
target cells using specialised junctions- synapses-acetylcholine.
4. Endocrine - long range signalling - hormones secreted into the
bloodstream - distributed throughout the body. Selective
effect mediated by receptor distribution. e.g insulin
Key concepts to think about –
o What are the differences in how quickly these transmission mechanisms act?
o Do you think the concentration of different types of intercellular signal will be different? How
easy is it to cause a large change in hormone concentration when only a few cells in the
pituitary might secrete hormone into litres of blood, compared to a neurotransmitter being
secreted into the tiny volume of a synapse?
o What sort of receptors do you think need to be able to detect these different kinds of signals?
What sort of features must they have?
Intracellular signalling enables integration of extracellular cues with the internal state of the cell (i.e.
signal processing)
• Cells are programmed to undergo only a limited number of fates in response to environmental
therefore need to:
1) decide which signals to prioritise and
2) weigh up these instructions against internal state.
,• The network of (mostly cytoplasmic) proteins enables this. Two major arms to cellular response:
— rapid using existing components occur through changing their conformation, post-translational
modification or changing their location
— slower events that depend on gene expression (transcription + translation) -> changes in protein
repertoire energetically costly -> most decisions are therefore made using existing components.
• Newly expressed gene products often modify the behavior of signalling pathways that originally caused
their expression (positive or negative feedback).
Each cell is programmed to respond to specific combinations of intercellular signals- BUT ONLY WHEN IT
IS APPROPRIATE. The cell will get inputs from all these sources and internal state of the cells. Cells must
have a specific receptor and signal recognition
mechanism for each signal to which they respond. The
outcome can be complex. e.g. involving coordination of
cell shape, cell movement, energy metabolism and gene
expression.
• Cells may respond to a range of signals
• Response to a signal is cell-type specific
• Each type of signal has a specific receptor
Signal transduction involves coordination between existing
molecules and newly-synthesised gene products
How do signals get across the cell?
Signals get across crowded cells using interaction relays or diffusion
of small molecules. The cell cytoplasm is packed with stuff -
Physically getting a signal from one place to another occurs by 2
major mechanisms:
1. Relays mediated by direct association of large molecules, e.g. enzyme relays, binding relays or active
transport:
• Enzyme relays
• Conformational change
• Translocation
2. Diffusion of small molecules (second messengers):
• Small molecules can rapidly diffuse.
• Typical second messengers include Ca2+, cAMP etc.
Signalling molecules are typically converted to an active form (or moved) and converted back to an inactive
form -> 'writers' and de-activating 'erasers'.
Several such reactions -> pathway. The
control of signalling pathways can be
simplified as controlling the 'writer' and/or
'eraser' function as each stage.
Almost all intracellular communication can be
simplified as a series of ‘writer’ and ‘eraser’
mechanisms.
, Introduction to second messengers
Ca2+, cAMP, cGMP, PI: all small - rapidly diffusible - converted to active forms (or transported) and equally
rapidly degraded/moved. They are not made or destroyed.
Major second messenger systems:
• Ca2+ ions- pumps and channels control ion flow in and out of cellular compartments.
• cyclic AMP and GMP- synthesised by cyclases, degraded by phosphodiesterases.
• Phosphoinositides- lipid kinases, lipid phosphatases and phospholipases control conversion from one
form to another
Phosphoinositide nomenclature and localisation:
Phosphatidylinositol(X,X,X)(bis/tris)phosphate PI(X,X,X)P(2/3)
PI = phosphatidyl inositol -> phospholipid -> glycerol backbone
inserted into membrane -> linked to a hydrophilic inositol ring with
OH groups at 5 positions -> can be phosphorylated on 3, 4, 5
positions by lipid kinases and removed by phosphatases in any
combination -> Nomenclature is: PI(3)P, PI(3,4)P2, PI(3,4,5)P3,
PI(3,5)P2 etc. numbers in brackets signify which position the phosphate group is on. When written, the 'bis'
or 'tris' affix signifies whether there are 2 or 3 phosphate groups on the ring.
• PI species typically diffuse within the membrane, while IP3 can diffuse through the cell.
Molecule synthesis and degradation control the speed and amplitude of cellular response
• Most signalling processes
(phosphorylation/dephosphorylation,
synthesis/degradation) undergo high rates of
turnover even when they are not stimulated.
This is because cells usually detect changes in
concentration of a signalling molecule (rather
than absolute level): changes in concentration
are more rapid if a molecule has higher rates of
turnover.
• Molecules made and destroyed all the time ->
high energy cost, but more rapidly responsive
or dynamic.
Many signalling molecules have very
high rates of turnover.
