Like intracellular metabolic pathways (discussed in Chapter 2) and the systems controlling gene activity (Chapter 7), most intracellular signaling systems incorporate feedback loops, in which the output of a process acts back to regulate that same process. We discussed the mathematical analysis of feedback loops in Chapter 8. In positive feedback, the output stimulates its own production; in negative feedback, the output inhibits its own production (Figure 15–17). Feedback loops are of great general importance in biology, and they regulate many chemical and physical processes in cells. Those that regulate cell signaling can either operate exclusively within the target cell or involve the secretion of extracellular signals. Here, we focus on those feedback loops that operate entirely within the target cell; even the simplest of these loops can produce complex and interesting effects.
Positive feedback in a signaling pathway can transform the behavior of the responding cell. If the positive feedback is of only moderate strength, its effect will be simply to steepen the response to the signal, generating a sigmoidal response like those described earlier; but if the feedback is strong enough, it can produce an all-or-none response (see Figure 15–15). This response goes hand in hand with a further property: once the responding system has switched to the high level of activation, this condition is often self-sustaining and can persist even after the 0.5 1.0 1.5 2.0 1 2 8 16 % of maximum activation of target protein an allosteric protein as a function of effector molecule concentration.
The curves show how the sharpness of the activation response increases with an increase in the number of allosteric effector molecules that must be bound simultaneously to activate the target protein. The curves shown are those expected, under certain conditions, if the 0 activation requires the simultaneous binding relative concentration of effector molecule of 1, 2, 8, or 16 effector molecules.
signal strength drops back below its critical value. In such a case, the system is said to be bistable: it can exist in either a “switched-off” or a “switched-on” state, and a transient stimulus can flip it from the one state to the other (Figure 15–18A and B).
Through positive feedback, a transient extracellular signal can induce longterm changes in cells and their progeny that can persist for the lifetime of the organism. The signals that trigger muscle-cell specification, for example, turn on the transcription of a series of genes that encode muscle-specific transcription regulatory proteins, which stimulate the transcription of their own genes, as well as genes encoding various other muscle-cell proteins; in this way, the decision to become a muscle cell is made permanent. This type of cell memory, which depends on positive feedback, is one of the basic ways in which a cell can undergo a lasting change of character without any alteration in its DNA sequence.
Studies of signaling responses in large populations of cells can give the false impression that a response is smoothly graded, even when strong positive feedback is causing an abrupt, discontinuous switch in the response in individual cells. Only by studying the response in single cells is it possible to see its all-or-none character (Figure 15–19). The misleading smooth response in a cell population is due to the random, intrinsic variability in signaling systems that we described earlier: all cells in a population do not respond identically to the same concentration of extracellular signal, especially at intermediate signal concentrations where the receptor is only partially occupied.
Negative Feedback is a Common Motif in Signaling Systems
By contrast with positive feedback, negative feedback counteracts the effect of a stimulus and thereby abbreviates and limits the level of the response, making the system less sensitive to perturbations (see Chapter 8). As with positive feedback, however, qualitatively different responses can be obtained when the feedback
Figure 15–17 Positive and negative feedback. In these simple examples, a stimulus activates protein A, which, in turn, activates protein B. Protein B then acts back to either increase or decrease the activity of A.