Biology Reference
In-Depth Information
depends on its ability to receive information and respond to
a constantly variable environment. Information is received
through the cell's signaling pathways. Information trans-
mittal through a pathway can often evoke a cellular
response. Such responses in the context of tissues and
organs can contribute to organismal behavior. A classic
example is the fight or flight response. In response to an
excitable threatening stimulus adrenaline is released into
the bloodstream. Adrenaline can bind to its receptor,
b
-adrenergic receptor, which activates the signaling trans-
ducer Gs, which in turn activates the enzyme adenylyl
cyclase which produces cAMP, a diffusible intracellular
second messenger. Through the cAMP-dependent protein
kinase (also known as PKA) cAMP, activates phosphory-
lase kinase (PhosK), which in turn activates glycogen
phosphorylase (GlyPhos), which phosphorylates glycogen
to catalyze the production of glucose-6-phosphatase, which
is eventually converted to free glucose that can be used for
energy metabolism in muscle. Thus this linear signaling
pathway (
Figure 16.1
A, blue outline) produces energy
required for the fight or flight response. In common
parlance this response is called the 'adrenaline rush'.
Epinephrine (adrenaline) and norepinephrine have
actions in many tissues and organs. In neurons
b
-adrenergic
receptors, activated by the neurotransmitter norephinephrine
through the second messenger cAMP regulate both PKA and
Epac, leading to the final activation of MAP-kinase 1, 2
[14,15]
(
Figure 16.1
A, red outline). AMP-GEF/Epac is
a guanine nucleotide exchange factor (GEF). The GEF
proteins promote the exchange of GDP for GTP on small
GTPases. cAMP binds to Epac to activate the small GTPases
RAP1A and RAP2A. Both PKA and MAPK in turn regulate
the phosphorylation and activation of the transcription factor
CREB
[16,17]
(
Figure 16.1
A). Many CREB-regulated genes
have been shown to be involved in learning and memory
processes
[18,19]
.
The bifurcation of cAMP signals in neurons and other
cell types where it can bind to and activate both PKA and
Epac, shows the origins of a signaling network where
a single signal (cAMP) can be routed to two different
protein kinases (PKA and MAP-kinase 1, 2). These protein
kinases have some common but also many different targets,
and thus the cAMP signal can be routed to many targets
within the cell.
Networks result from interconnections between
signaling pathways. A certain signaling molecule can
receive signals from multiple inputs. A small G protein
such as Ras and a transcription factor, such as CREB, are
examples of signaling proteins that receive signaling from
multiple upstream pathways. Such signaling molecules can
be considered as junctions that integrate signals. There are
also molecules that route signals to multiple pathways.
cAMP is one such molecule that can split signals to control
multiple downstream pathways
[20]
.
We can think of the mammalian cell as a complex
network of signaling pathways resembling the network of
different subway lines that form the New York City subway
system (
Figure 16.1
B): focusing on a few subway lines or
on a single station would give the observer only a partial
idea of how the city works as people move from one place
to another for work or other activities (
Figure 16.1
B). It
would also not provide us with a realistic estimate of the
number of people who take the subway every day. In order
to get a more complete sense of the real number of people
who ride the subway (estimated to be approximately 4.3
million every day, and
1 billion people per year!), one
should consider the entire network of about 24 subway
lines that form one of the largest subway systems in the
world (
Figure 16.1
B, right panel). Similarly, in order to
understand how the dynamics of signaling within the cell
lead to coordination between multiple cellular functions,
one needs to look at the entire network of signaling path-
ways and how they connect and regulate the various
cellular machines in a synchronized manner. The multi-
plicity of signaling pathways and networking originates
with the extracellular signals. Epinephrine and norepi-
nephrine bind to three classes of receptors, the
b
-adren-
ergic,
a
1
-adenergic and
a
2
-adrenergic, which specifically
couple to the Gs, Gq/11 and Gi/o pathways. Indeed, most
natural ligands for G protein-coupled receptors bind to
multiple classes of receptors which through different G
protein-dependent pathways control many cellular
processes that in turn regulate numerous physiological
processes (
Figure 16.1
C).
Interactions between G protein pathways occur at
multiple levels. Several G protein-coupled receptors interact
withmultiple heterotrimeric Gproteins, and the downstream
effectors can also serve as junctions between the different G
protein pathways. The pathways are sufficiently inter-
connected that together they form a network. Such
connectivity to formhighly coupled networks has functional
consequences. One of these is seen in drug
>
target interac-
tions
[21]
. We can readily observe a visible cluster in the
network between FDA-approved drugs and their targets
(
Figure 16.1
D) as nearly 50% of all FDA approved drugs
have G protein-coupled receptors as targets.
Although the description above has focused on G
protein-coupled receptors, many other receptors, such as
the growth factor receptors (receptor tyrosine kinases), ion
channel receptors in the nervous systems, cytokine recep-
tors and several other types of receptors, including nuclear
receptors, are all interconnected.
One of the best examples where networking begins at
the level of the receptor is the receptor tyrosine kinase
[22
e
24]
(
Figure 16.2
), which network can transmit growth
factor signals through many different pathways. Such
routing can regulate multiple independent cellular func-
tions; also, signal routing through multiple pathways can
e
