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

SIGNALING THROUGH ENZYME-COUPLED RECEPTORS
857
CYTOSOL
scaffold 1
(A)
mating factor
kinase A
kinase B
kinase C
MATING RESPONSE
MAP kinase kinase kinase
MAP kinase kinase
MAP kinase
osmolarity-sensing
receptor
high osmolarity
kinase A
kinase domain
kinase D
GLYCEROL SYNTHESIS
give responses that are either graded or switchlike and either brief or long lasting.
In an example illustrated earlier, in Figure 15–19, MAP kinase activates a complex
positive feedback loop to produce an all-or-none, irreversible response when frog
oocytes are stimulated to mature MBoC6 by m15.61/15.50
a brief exposure to the extracellular signal
molecule progesterone. In many cells, MAP kinases activate a negative feedback
loop by increasing the concentration of a protein phosphatase that removes the
phosphate from MAP kinase. The increase in the phosphatase results from both
an increase in the transcription of the phosphatase gene and the stabilization of
the enzyme against degradation. In the Ras–MAP-kinase pathway shown in Figure
15–49, Erk also phosphorylates and inactivates Raf, providing another negative
feedback loop that helps shut off the MAP kinase module.
(B)
scaffold 2
Figure 15–50 The organization of two
MAP kinase modules by scaffold
proteins in budding yeast. Budding
yeast have at least six three-component
MAP kinase modules involved in a variety
of biological processes, including the
two responses illustrated here—a mating
response and the response to high
osmolarity. (A) The mating response is
triggered when a mating factor secreted
by a yeast of opposite mating type binds
to a GPCR. This activates a G protein, the
βγ complex of which indirectly activates
the MAPKKK (kinase A), which then relays
the response onward. Once activated, the
MAP kinase (kinase C) phosphorylates
and thereby activates several proteins that
mediate the mating response, in which the
yeast cell stops dividing and prepares for
fusion. The three kinases in this module
are bound to scaffold protein 1. (B) In a
second response, a yeast cell exposed to a
high-osmolarity environment is induced to
synthesize glycerol to increase its internal
osmolarity. This response is mediated by
an osmolarity-sensing receptor protein and
a different MAP kinase module bound to
a second scaffold protein. (Note that the
kinase domain of scaffold 2 provides the
MAPKK activity of this module.) Although
both pathways use the same MAPKKK
(kinase A, green), there is no cross-talk
between them because the kinases in each
module are bound to different scaffold
proteins, and the osmosensor is bound to
the same scaffold protein as the particular
kinase it activates.
Scaffold Proteins Help Prevent Cross-talk Between
Parallel MAP Kinase Modules
Three-component MAP kinase signaling modules operate in all eukaryotic cells,
with different modules mediating different responses in the same cell. In budding
yeast, for example, one such module mediates the response to mating
pheromone, another the response to starvation, and yet another the response to
osmotic shock. Some of these MAP kinase modules use one or more of the same
kinases and yet manage to activate different effector proteins and hence different
responses. As discussed earlier, one way in which cells avoid cross-talk between
the different parallel signaling pathways and ensure that each response is specific
is to use scaffold proteins (see Figure 15–10A). In budding yeast cells, such scaffolds
bind all or some of the kinases in each MAP kinase module to form a complex
and thereby help to ensure response specificity (Figure 15–50).
Mammalian cells also use this scaffold strategy to prevent cross-talk between
different MAP kinase modules. At least five parallel MAP kinase modules can
operate in a mammalian cell. These modules make use of at least 12 MAP kinases,
7 MAPKKs, and 7 MAPKKKs. Two of these modules (terminating in MAP kinases
called JNK and p38) are activated by different kinds of cell stresses, such as ultraviolet
(UV) irradiation, heat shock, and osmotic stress, as well as by inflammatory
cytokines; others mainly mediate responses to signals from other cells.
Although the scaffold strategy provides precision and avoids cross-talk, it
reduces the opportunities for amplification and spreading of the signal to different
parts of the cell, which require at least some of the components to be diffusible. It
is unclear to what extent the individual components of MAP kinase modules can
dissociate from the scaffold during the activation process to permit amplification.