Adaptation to a signal molecule can occur in various ways. It can result from inactivation of the receptors themselves. The binding of signal molecules to cell-surface receptors, for example, may induce the endocytosis and temporary sequestration of the receptors in endosomes. In some cases, such signal-induced receptor endocytosis leads to the destruction of the receptors in lysosomes, a process referred to as receptor down-regulation (in other cases, however, activated receptors continue to signal after they have been endocytosed). Receptors can also become inactivated on the cell surface—for example, by becoming phosphorylated—with a short delay following their activation. Adaptation can also occur at sites downstream of the receptors, either by a change in intracellular signaling proteins involved in transducing the extracellular signal or by the production of an inhibitor protein that blocks the signal transduction process. These various adaptation mechanisms are compared in Figure 15–20.
Though bewildering in their complexity, the multiple cross-regulatory signaling pathways and feedback loops that we describe in this chapter are not just a haphazard tangle, but a highly evolved system for processing and interpreting
Figure 15–19 The importance of examining individual cells to detect all-or-none responses to increasing concentrations of an extracellular signal. In these experiments, immature frog eggs (oocytes) were stimulated with increasing concentrations of the hormone progesterone. The response was assessed by analyzing the activation of MAP kinase (discussed later), which is one of the protein kinases activated by phosphorylation in the response. The amount of phosphorylated (activated) MAP kinase in extracts of the oocytes was assessed biochemically. In (A), extracts of populations of stimulated oocytes were analyzed, and the activation of MAP kinase appeared to increase progressively with increasing progesterone concentration. There are two possible ways of explaining this result: (B) MAP kinase could have increased gradually in each individual cell with increasing progesterone concentration; or (C) individual cells could have responded in an all-or-none way, with the gradual increase in total MAP kinase activation reflecting the increasing number of cells responding with increasing progesterone concentration. When extracts of individual oocytes were analyzed, it was found that cells had either very low amounts or very high amounts, but not intermediate amounts, of the activated kinase, indicating that the response was essentially all-or-none at the level of individual cells, as diagrammed in (C). Subsequent studies revealed that this allor-none response is due in part to strong positive feedback in the progesterone signaling system. (Adapted from J.E. Ferrell and E.M. Machleder, Science 280:895– 898, 1998. With permission from AAAS.)
Figure 15–20 Some ways in which target cells can become adapted (desensitized) to an extracellular signal molecule.
The mechanisms shown here that operate at the level of the receptor often involve phosphorylation or ubiquitylation of the receptor proteins.
the vast number of signals that impinge upon animal cells. The whole molecular control network, leading from the receptors at the cell surface to the genes in the nucleus, can be viewed as a computing device; and, like that other biological computing device, the brain, it presents one of the hardest problems in biology. We can identify the components and discover how they work individually. We can understand how small subsets of components work together as regulatory modules, noise filters, or adaptation mechanisms, as we have seen. However, it is a much more difficult task to understand how the system works as a whole. This is not only because the system is complex; it is also because the way in which it behaves is strongly dependent on the quantitative details of the molecular interactions, and, for most animal cells, we have only rough qualitative information. A major challenge for the future of signaling research is to develop more sophisticated quantitative and computational methods for the analysis of signaling systems, as described in Chapter 8.