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

PRINCIPLES OF CELL SIGNALING
829
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
(A)
(B)
activity of E kinase
time
time
signal kinase
S
E
inactive
E kinase
CONTROL:
NO FEEDBACK
POSITIVE
FEEDBACK
POSITIVE FEEDBACK
I
positive
feedback
P
E
SIGNAL
SIGNAL
activated
E kinase
(D)
activity of E kinase
CONTROL:
NO FEEDBACK
time
NEGATIVE
FEEDBACK
SHORT DELAY
time
NEGATIVE
FEEDBACK
LONG DELAY
time
signal kinase
S
E
highly active
I phosphatase
(C)
NEGATIVE FEEDBACK
I
P
P
E
negative
feedback
SIGNAL
SIGNAL
SIGNAL
activated
E kinase
DELAY
stimulus A B
+
positive feedback
stimulus A B
–
negative 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.
MBoC6 m15.26/15.17
Figure 15–18 Some effects of simple
feedback. The graphs show the computed
effects of simple positive and negative
feedback loops (see Chapter 8). In each
case, the input signal is an activated protein
kinase (S) that phosphorylates and thereby
activates another protein kinase (E); a
protein phosphatase (I) dephosphorylates
and inactivates the activated E kinase. In
the graphs, the red line indicates the activity
of the E kinase over time; the underlying
blue bar indicates the time for which the
input signal (activated S kinase) is present.
(A) Diagram of the positive feedback
loop, in which the activated E kinase acts
back to promote its own phosphorylation
and activation; the basal activity of the I
phosphatase dephosphorylates activated
E at a steady, low rate. (B) The top graph
shows that, without feedback, the activity
of the E kinase is simply proportional (with a
short lag) to the level of stimulation by the S
kinase. The bottom graph shows that, with
the positive feedback loop, the transient
stimulation by S kinase switches the
system from an “off” state to an “on” state,
which then persists after the stimulus has
been removed. (C) Diagram of the negative
feedback loop, in which the activated E
kinase phosphorylates and activates the I
phosphatase, thereby increasing the rate at
which the phosphatase dephosphorylates
and inactivates the phosphorylated E
kinase. (D) The top graph shows, again,
the response in E kinase activity without
feedback. The other graphs show the
effects on E kinase activity of negative
feedback operating after a short or long
delay. With a short delay, the system shows
a strong, brief response when the signal
is abruptly changed, and the feedback
then drives the response back down to a
lower level. With a long delay, the feedback
produces sustained oscillations for as long
as the stimulus is present.