• Many bacteria can release and sense chemical signals
  
• Signalling b/w yeast cells prepares them to mate
  
• Signalling b/w ameboid cells can cause them to aggregate e.g. Dictyostellium cells come together to form a fruiting body in order to have spores spreading to other areas.
  

mammals, flies and worms have similar communication pathways

• signals are sent out in different forms: proteins, small peptides, nucleotides, dissolved gases, etc.
  
• signals are sent out in different ways: by exocytosis, diffusion, displaying on cell surface
  

• signals can bind to surface receptor proteins if they are hydrophilic (cannot pass the hydrophobic membrane)
  
• signals can be transported on carrier proteins and then bind a intracellular receptor if they are hydrophobic
  
• more combinations are possible

• signalling molecules on the signalling cell must be directly in contact with the receptor on the target cell (e.g. Notch signal)
  
• signals are retained on the cell surface
  

• signals are released and diffused away but only act locally
  
• signals are restricted due to:
  
• • internalization by neighbouring cells
  • signal instablized or destroyed by extraceullar enzymes
  • signals bind to extracellular matrix molecules

in nervous system, neurons extend axons to contact distant target cells — the long range is due to the long length of the axons

but the released signalling molecules only act locally at target

hormones are released into the bloodstream and carried to target far away

Cells have signal transduction pathways to respond to extracellular signals

     Signal transduction: conversion of extracellular signal to intracellular signal (or in general, any type of signal converted to another type)

     Effector: a downstream molecule in a signal transduction pathway —> upstream molecuels have effects on them

Between extracellular signal and the final effector proteins, there are small intracellular signalling molecules or large intracellular signalling molecules. —> both bind to their downstream molecule and change their conformation in some way.

• Scafold protein: draws together multiple signalling components in order to increase      efficiency and specificity
  
• Relay: sends signal downstream in the same basic form —> no alteration, no transduction (e.g.protein-protein interactions)
  
• Transduce and amplify: signals are converted into different forms. If there’s a protein, the one protein can convert many downstream targets and thus amplifying them
  
• Integrate: coordinate and combine signals from different sources —> when more than one signal is required to activate downstream targets (coincidence detector makes sure that all the requirements are met)
• Spread: sends signals to other pathways
• Anchor: restricts signals to certain part of the cell —> localizing signalling event
• Modulate: inhibits signals to restrict the intensity of signalling (= down-regulation)

• One of the most important signalling process in humans.
  
• Phosphate groups are added by protein kinases, and removed by protein phosphatases.
  
• There are serine/threonine kinases and tyrosine kinases: they residues have -OH groups on them where phosphate groups can be added on
  
• signal comes in —> protein kinase uses the phosphate group on ATP and add it onto the target protein —> the conformation of the phosphrylated protein is changed —> sends a signal to the downstream targets —> when the signal is not in use, protein phosphatase removes the phosphate group and turns the protein off

• There are large trimeric and small monomeric types
• They have low GTPase activity by themselves, so they needs extra helpers: GAPs and GEFs
• • GAPs = GTPase activating preteens increase GTP hydrolysis
  • GEFs = Guanine nucleotide exchange factors remove GDP and allow GTP to bind
• signal comes in —> GEF removes GDP, allowing new GTP to bind —> conformation of the protein is changed —> sends a signal to the downstream targets  —> when the signal is not in use, GAP promotes GTP hydrolysis and turns the protein 

Protein interaction

Proteins often contain one or more interaction domains. A single polypeptide chain can have multiple folded semi-automic domains that have different properties and binding characteristics.(e.g. SH2, PTB, PH, SH3)

During evolution, domains can be added or switched to alter interactions and re-wire signalling pathways.

1) Have short range signalling so that the signals can act directly to the local target

2) Synaptic signalling: neurons make connection only to its target cells. Once the links are made, specificity can be maintained.

3) Endocrine signalling: the signalling molecules can only bind to specific receptors on the target cells. The same signalling molecule can act on different cell types as long as the right type of receptors exist on the targets. (e.g. acetylcoline acting on heart muscle and skeletal muscle cells: both cell types have receptors that bind to acetylcoline, but their downstream machinery is different so the response is different)

There are numerous pathways interacting with one another inside the cells, so what prevents the upstream signals from activating all the possible downstream targets?

1) Preformed signalling complexes on a scaffold protein:Scaffold proteins assemble the target intracellular signalling proteins ahead of time, and when a signal molecule activates the receptor, the activated local complex is forced to work together to activate downstream signals even if they might be able to activate other targets had they been separated.

* the activation pattern is forced to be: 1 —> 2—> 3 because of their proximity

2) Assembly of signalling complex on  an activated receptor: Signal binding to receptor induces the assemble of intracellular signalling proteins onto the activated receptors —> downstream signals

3) Assembly of signalling complex on phosphoinositide (PIP) docking sites: signal-receptor complex activates local PIPs, PIPs can bring together specific proteins —> downstream signals

Combination of different signals can lead to multiple outcomes

Coincidence detectors only activate downstream signals when two upstream signals are both detected. —> One signal phosphorylates one side, another one phosphorylates another.

primary cilia: some key signalling pathways are found inside these: —> insulating the pathway from the rest of the cell

synapses: insulating the signalling complex

synaptic signalling: very fast

endocrine signally: relatively slow due to the speed of blood flow

response speed to a signal can be slow or fast depending on the availability of cellular machinery: whether or not it has been built.

positive or negative —> downstream pathway activated + promotion or inhibition of the loop

positive feedback leads to a long lasting signal, and if it’s strong enough, can become self sustaining so that the system is kept at high activation even when the signal is lost.

e.g. when cells differentiate, signal F and G contributes to the self-sustaining of differentiation

negative feedback: duration of the signal is maintained. If feedback occurs quickly, signalling is suppressed. Allows cells to respond to a range of signal strengths

system can adapt to the activation so there needs to be more activation to boost signal.

slow negative feedback can make the system oscillate. —> the delay from signalling to inhibiting signalling creates the pattern.