Principles of cell signaling - UT Southwestern
Principles of cell signaling - UT Southwestern
Principles of cell signaling - UT Southwestern
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39057_ch14_<strong>cell</strong>bio.qxd 8/28/06 5:11 PM Page 607<br />
Second<br />
messenger<br />
3':5'-cyclic AMP<br />
(cAMP)<br />
RNA polymerase<br />
Magic spot<br />
(ppGpp, ppGppp) ObgE transcription<br />
arrest<br />
detector<br />
Cyclic di-GMP<br />
phosphodiesterase<br />
Inositol-1,3,5-<br />
trisphosphate<br />
(IP 3 )<br />
Diacylglycerol<br />
(DAG)<br />
Phosphatidyl-<br />
inositol-4,5-<br />
bisphosphate<br />
(PIP 2 )<br />
3':5'-Cyclic GMP<br />
(cGMP)<br />
Cyclic ADP-ribose<br />
Nitric oxide (NO. )<br />
Ca2+<br />
Cyclic<br />
diguanosinemonophosphate<br />
Phosphatidyl-<br />
inositol-3,4,5-<br />
trisphosphate<br />
Adenylyl<br />
Protein kinase A<br />
cyclase<br />
Bacterial transcription<br />
factors<br />
Cation channel<br />
Cyclic nucleotide<br />
phosphodiesterase<br />
Rap GDP/GTP<br />
exchange factor<br />
(Epac)<br />
IP 3 -gated Ca 2+<br />
channel<br />
Protein<br />
kinase C<br />
Trp cation<br />
channel<br />
Ion channel<br />
Transporters<br />
Protein kinase G<br />
Ca2+ channel<br />
Various two<br />
component<br />
system proteins<br />
Guanylyl cyclase<br />
Numerous<br />
calmodulin<br />
Akt (protein<br />
kinase B)<br />
Second messengers<br />
Targets<br />
Other PH<br />
domains/proteins<br />
Synthesis/<br />
Release<br />
Rel1A<br />
SpoT<br />
Cation channel<br />
Cyclic nucleotide<br />
phosphodiesterase<br />
Phospholipase<br />
C<br />
Phospholipase<br />
C<br />
PIP 5-kinase<br />
Guanylyl<br />
cyclase<br />
ADP-ribose<br />
cyclase<br />
Diguanylate<br />
cyclase<br />
PI 3-kinase<br />
GTP<br />
PIP 2<br />
PIP 2<br />
PI-4-P<br />
GTP<br />
NAD<br />
GTP<br />
Stored<br />
Ca2+<br />
PIP 2<br />
phosphatidylinositol-4,5-diphosphate, sphingosine-1-phosphate<br />
and phosphatidic acid.<br />
The first <strong>signaling</strong> compound to be described<br />
as a second messenger was cAMP. The name<br />
arose because cAMP is synthesized in animal<br />
<strong>cell</strong>s as a second, intra<strong>cell</strong>ular signal in response<br />
to numerous extra<strong>cell</strong>ular hormones, the first<br />
messengers in the pathway. cAMP is used by<br />
prokaryotes, fungi, and animals to convey information<br />
to a variety <strong>of</strong> regulatory proteins.<br />
(Its occurrence in higher plants has still not been<br />
proved.)<br />
Adenylyl cyclases, the enzymes that synthesize<br />
cAMP from ATP, are regulated in various<br />
ways depending on the organism in which<br />
they occur. In animals, adenylyl cyclase is an<br />
integral protein <strong>of</strong> the plasma membrane whose<br />
multiple is<strong>of</strong>orms are stimulated by diverse<br />
agents (see Figure 14.13). In animal <strong>cell</strong>s, adenylyl<br />
cyclase is generally stimulated by G s<br />
, which<br />
was originally discovered as an adenylyl cyclase<br />
regulator. Some fungal adenylyl cyclases are<br />
also stimulated by G proteins. Bacterial cyclases<br />
are far more diverse in their regulation.<br />
cAMP is removed from <strong>cell</strong>s in two ways.<br />
It may be extruded from <strong>cell</strong>s by an ATP-driven<br />
anion pump but is more <strong>of</strong>ten hydrolyzed to 5′-<br />
AMP by members <strong>of</strong> the cyclic nucleotide phosphodiesterase<br />
family, a large group <strong>of</strong> proteins<br />
that are themselves under multiple regulatory<br />
controls.<br />
The prototypical downstream regulator for<br />
cAMP in animals is the cAMP-dependent protein<br />
kinase, but a bacterial cAMP-regulated transcription<br />
factor was discovered shortly thereafter,<br />
and other effectors are now known (Figure<br />
14.14). The cAMP system remains the prototypical<br />
eukaryotic <strong>signaling</strong> pathway in that its<br />
components exemplify almost all <strong>of</strong> the recognized<br />
varieties <strong>of</strong> <strong>signaling</strong> molecules and their<br />
interactions: hormone, receptor, G protein,<br />
adenylyl cyclase, protein kinase, phosphodiesterase,<br />
and extrusion pump.<br />
The second messenger-stimulated protein<br />
kinase PKA is a tetramer composed <strong>of</strong> two catalytic<br />
(C) subunits and two regulatory (R) subunits,<br />
as illustrated in FIGURE 14.15. The R subunit<br />
binds to the catalytic subunit in the substratebinding<br />
region, maintaining C in an inhibited<br />
state. Each R subunit binds two molecules <strong>of</strong><br />
cAMP, four cAMP molecules per PKA holoenzyme.<br />
When these sites are filled, the R subunit<br />
dimer dissociates rapidly, leaving two free catalytic<br />
subunits with high activity. The difference<br />
in affinity <strong>of</strong> R for C in the presence and absence<br />
<strong>of</strong> cAMP is ~10,000-fold. The strongly cooperative<br />
binding <strong>of</strong> cAMP generates a very steep<br />
activation curve with an apparent threshold below<br />
which no significant activation <strong>of</strong> PKA occurs,<br />
as illustrated in Figure 14.15. PKA activity,<br />
thus, increases dramatically over a narrow range<br />
<strong>of</strong> cAMP concentrations. PKA is also regulated<br />
Precursor<br />
Removal<br />
Phosphodiesterase<br />
ATP<br />
Organic<br />
anion<br />
transporter<br />
SpoTcatalyzed<br />
hydrolysis<br />
Phosphatase<br />
Diacylglycerol<br />
kinase<br />
Diacylglycerol<br />
lipase<br />
Phospholipase<br />
C<br />
Phosphatase<br />
Phosphodiesterase<br />
Hydrolysis<br />
NO . synthase arginine Reduction<br />
Release from<br />
storage<br />
organelles<br />
or plasma<br />
membrane<br />
channels<br />
Reuptake<br />
and<br />
extrusion<br />
pumps<br />
Phosphatase<br />
FIGURE 14.14 Major second messengers, some <strong>of</strong> the proteins that they regulate,<br />
their sources and their disposition.<br />
14.14 Second messengers provide readily diffusible pathways for information transfer 607