Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

830 Chapter 15: Cell Signaling
MAP kinase activation (%)
(A)
100
75
50
25
0
0
0.001 0.01 0.1 1
progesterone (µM)
10
operates more powerfully. A delayed negative feedback with a long enough delay
can produce responses that oscillate. The oscillations may persist for as long as the
stimulus is present (Figure 15–18C and D) or they may even be generated spontaneously,
without need of an external signal to drive them. Many such oscillators
also contain positive feedback loops that generate sharper oscillations. Later in
this chapter, we will encounter specific examples of oscillatory behavior in the
intracellular responses to extracellular signals; all of them depend on negative
feedback, generally accompanied by positive feedback.
If negative feedback operates MBoC6 m15.24/15.19
with a short delay, the system behaves like a
change detector. It gives a strong response to a stimulus, but the response rapidly
decays even while the stimulus persists; if the stimulus is suddenly increased,
however, the system responds strongly again, but, again, the response rapidly
decays. This is the phenomenon of adaptation, which we now discuss.
Cells Can Adjust Their Sensitivity to a Signal
In responding to many types of stimuli, cells and organisms are able to detect the
same percentage of change in a signal over a wide range of stimulus strengths.
The target cells accomplish this through a reversible process of adaptation, or
desensitization, whereby a prolonged exposure to a stimulus decreases the cells’
response to that level of stimulus. In chemical signaling, adaptation enables cells
to respond to changes in the concentration of an extracellular signal molecule
(rather than to the absolute concentration of the signal) over a very wide range
of signal concentrations. The underlying mechanism is negative feedback that
operates with a short delay: a strong response modifies the signaling machinery
involved, such that the machinery resets itself to become less responsive to the
same level of signal (see Figure 15–18D, middle graph). Owing to the delay, however,
a sudden increase in the signal is able to stimulate the cell again for a short
period before the negative feedback has time to kick in.
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
(B)
(C)
increasing concentration of progesterone
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.)