Signal Transduction: How Cells Process Thousands of Signals

[phaser88]

I don't understand why cells have thousands of different receptors which then exert their effects through the same few intracellular pathways.

For example, I know that many different neuromodulators which act through metabotropbic receptors exert their effects on cAMP, which then exerts effects on gene regulation, but then numerous other unrelated things like lactose also exert their effects through cAMP.

Do all of these signals get crossed and confused, or does it somehow work out? If there is an article or book that explains how this all works, I would be interested.

 

[Andy Resnick]

I've wondered this myself- the same issue occurs with pathways using Ca++ as a second messenger.

When I asked a senior colleague, he said something like "Some folks claim it's microdomains", but it was clear he thought that model was silly.

http://en.wikipedia.org/wiki/Calcium_concentration_microdomains

 

[mishrashubham]

Nice question. We had a class on Peptide hormones a few days ago, and it's a shame this didn't cross my mind. She said that the G proteins bound to the receptors increase or decrease cAMP and others use messengers such as Ca++ and IP3. However we did not study the mechanism in detail. I would like to know what exactly the answer is.

 

[mishrashubham]

Alright, I checked with my teacher and she recommended looking up the chapter on signal transduction in Lubert Stryer's Biochemistry textbook. It seems that such mix ups do happen and the term is called "Crosstalk".

http://en.wikipedia.org/wiki/Crosstalk_(biology)

 

[Ygggdrasil]

Although the question of how cell signalling pathways maintain their specificity is still a question requiring much research, biologists have been able to define some mechanisms that keep signals from different signalling pathways from activating inappropriate responses.

One model system for studying such crosstalk are the yeast mitogen-activated protein kinase (MAPK) signalling pathways. In yeast, there are a number of different cell surface receptors (that respond to different stimuli) that activate a the family of MAPKs that in turn, activate different cellular responses. Interestingly, one of these MAPKs, Ste11, is shared between both the mating pheromone response pathway and the high osmolarity response pathway. Yet, mating pheromone does not activate the high osmolarity response and high osmolarity does not evoke the mating pheromone response. So, if Ste11 can be activated by either the mating pheromone pathway and the high osmolarity pathway, and it can turn on the responses to both pathways, what keeps the lines of communication from getting crossed?

It turns out that Ste11 is part of a two very different, large protein complex. In both of these complexes, a protein, called a scaffold protein, tethers Ste11's activity to the members of the signalling pathway directly before and after it. So, the mating pheromone receptor can activate Ste11 only if it is associated with the scaffold protein associated with the mating pathway, Ste5. Furthermore, when Ste11 is associated with Ste5, Ste5 allows Ste11 to activate only the downstream effectors of the mating pathway and does not allow Ste11 to activate any effectors of the osmolarity pathway. Pbs2, the scaffold protein associated with the osmolarity pathway, enforces a similar ordering of signalling events on Ste11 except with the proteins involved in the osmolarity pathway. Wendell Lim's group at UCSF demonstrated the importance of these scaffold proteins in regulating the specificity of MAPK signalling by showing that they could rewire these signalling pathways by reengineering the scaffold proteins (Park SH, Zarrinpar A, Lim WA (2003) Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms. Science 299:1061–1064 http://dx.doi.org/10.1126/science.1076979 PMC3117218).

While this answer is fairly specific to the MAPK signalling problem, it does demonstrate the general principle that controlling protein localization, for example, by joining members of a signalling pathway together via protein-protein interactions or by confining the signalling molecules to specific subcellular regions, is one mechanism by which cells prevent crosstalk between signalling pathways. The problem is obviously more complicated when you consider the small, quickly diffusing second messenger molecules like Ca²⁺ or cAMP, however.

 

[phaser88]

Thank you mishrashubham and Ygggdrasil.

 

[Ken Natton]

Hmmm, let me echo that. There is, of course, nothing I can contribute to this thread, but I am beginning to believe more strongly in the importance of acknowledging and expressing appreciation for the contributions of the experts. As a complete layman, there are times when this particular forum leaves me feeling that I am clinging to the back of the boat by my fingertips as we are about to go off another set of rapids. I am still struggling with metabolic pathways and classifications of types of mutation and now I have the concept of signal transduction to try to get some sense of, and in particular, this diagram. But don’t worry about me. You guys carry on. If I lose you I’ll just swim to the bank and walk down.