Introduction to cell signalling (part 1)

A particular interest of mine is cell signalling. This is the field of molecular biology that looks at how biochemical events in the cell go on to cause responses elsewhere in the same cell, and in other cells. Signals may be triggered by some aspect of the environment – the senses, or chemicals produced by invading pathogens, for example – and are propagated by a variety of mechanisms – hormones and neuronal action potentials over long distances; reversible chemical modifications activating enzymes in cascades, or releasing stores of small molecules within the cell. These details of the mechanisms are not important. With signalling I had barely got my feet wet before I was pushed into the depths working as a research assistant on a particular aspect of signalling in a cancer. I therefore quickly picked up a lot about these mechanisms.

But I was very confused. In my cells, response X to drug A is dependent on MAPK – one of a series of postal workers who handle the signal (just the first of today's bad analogies). But so is response Y. And response Z to drug B. And my colleague is working on a different cancer in a different cell type in a different species, which doesn't even respond to drugs A or B, but which is still doing things with MAPK! This would be fine if MAPK really were like a postal worker: it could pass on as many signals as it liked. But MAPK is not just the medium, it is the signal: it has an off and an on state, a zero and one. This confusion was not remedied when I was taught signalling formally in a final year undergraduate module. We were taught the pathways that propagate the signal from its cause to its effect (the cause and effect themselves were largely glossed over). There was the MAPK family of pathways, membrane derived messengers, cyclic AMP, and calcium ion pathways. But this was just rote learning of facts, not an introduction to themes and concepts. The concept of "cross-talk" was briefly introduced: the different pathways are able to interact and influence each other. But this concept is itself misleading.

It is often difficult to distinguish between cause, intermediate signals and response. A convenient “unit of history” may be defined as the period starting shortly after the assassination of Franz Ferdinand and ending with the Treaty of Versailles. During this unit, a large number of interacting intermediate events led from the assassination to the treaty. But this unit of history is not self-contained: World War I had many different causes converging, and many different effects diverging afterwards. History is not just a series of causes and effects, but a network of interacting causes and effects.

Lets look at the “responses” to signals. A typical “response” may be to alter the rate of expression of a set of genes. But gene expression itself resembles signalling in many ways: a cascade of recruitment of protein-based machinery to the gene and intermediates, and chemical modifications to other bits of machinery to modify their activity. In many cases, the gene product may itself be classified as a signalling molecule, going on to activate further pathways. Another response may be to release (or re-stock) stores of sugars (and fat), and again, some aspects of this process are hard to distinguish from the signalling itself, and the result – altering the concentration of sugars in the cell – may have effects on some of the other ongoing signalling events. Other “responses” may be to proceed with (or halt) cell division (itself a series of signalling and expression events); or to secrete some proteins out of the cell, where they may be picked up by neighbouring cells, or end up in the blood, where they are picked up by distant cells (where, of course, they go on to activate further signalling).

When we think about signalling (and when it is taught), we tend to think about it in terms of distinct packets, with a cause and an effect, and a series of intermediates. But like history, this can be a misleading way of thinking, especially when the events occurring before and after this packet are themselves complicated and important. To talk of "cross-talk" between historical events would also be misleading: it would suggest a number of distinct moments when the otherwise discreet parallel cascades of historical events were able to influence each other. Signalling, like history, is a network of interacting events. Dividing signalling into units is useful for studying it, but only if you understand that what you are looking at is a simplified model, and not the complete picture.