Biology Reference
In-Depth Information
FIGURE 16.2 The EGF e receptor signaling net-
work. Interactions of multiple effectors such as adaptors
(Grb2), enzymes (PLC- g ) transcription factors (Stat3)
lead to a complex intracellular signaling network that
can regulate multiple cellular processes
including
cytoskeletal dynamics,
cell
cycle
and apoptosis
(reprinted with permission from [23] ).
outputs. The GEFs for Ras display the value of having
multiple isoforms. The Ras-GEF called Sos communicates
signals from growth factor receptor pathways [27] .In
contrast DAG-stimulated GEFs can activate Ras in response
to signals from Gq/11 or Gi/o coupled pathways. [28] .
An early example where isoforms enable integration is
seen with mammalian adenylyl cyclases. There are 10 ade-
nylyl cyclase isoforms that produce cAMP in response to
signals from Gs-coupled receptors in response to Ca 2 รพ from
voltage gated calcium channels or glutamate-activated
channels such as the NMDA receptors. Additionally, the
production of cAMP can be inhibited by signals from Gi/o-
coupled receptors and activated throughPKCby signals from
Gq-coupled receptors, depending on which isoform of ade-
nylyl cyclase is present. This is summarized in Figure 16.3 ,
adapted from a review published in 1993 by Pieroni et al.
[20,29] . Isoform-dependent integration serves as a gauge to
balance signals coming frommany different receptors. In this
way signaling information coming from junctions are routed
towards different downstream cascades in such a way that
they can in turn regulate numerous physiological events, as in
the case of protein kinase A ( Figure 16.3 ).
apposition to the active zone of the synapse and the docked
synaptic vesicles in the presynaptic terminal. This location
places the PSD directly in the path of the ionic fluxes and
second- messenger cascades generated by neurotransmit-
ters. The PSD functions as a structural matrix, which clusters
ion channels in the postsynaptic membrane [30
32] and
anchors signaling molecules such as protein kinases and
phosphatases at the synapse [33] . Such anchoring has been
shown to be important for the signaling events that underlie
synaptic plasticity [34,35] .
Awell-known class of proteins called AKAPs (A-kinase
anchoring proteins) functions as a scaffold for signaling
networks [36
e
38] and assembles protein kinases and
phosphatases to interact with receptors and channels.
AKAPs provide a spatial dimension to signaling by forming
signaling complexes that have the intrinsic capability to both
consolidate and dissipate biochemical signals [20] . AKAPs
themselves are targeted to distinct regions of the cell.
Another major class of scaffolding proteins is the PDZ
domain-containing proteins that are central organizers of
protein complexes at the plasma membrane of the gluta-
matergic synapses [39,40] . PDZ domain proteins often
anchor channels and receptors to the postsynaptic density
and interact with other scaffold proteins. AKAPs bind to
PDZ domain-containing proteins PSD-95 and SAP-97,
a critical step for the targeting of protein kinase A to AMPA
receptors [41] .
Typically scaffold proteins possess bidirectional speci-
ficity: they specifically recognize one or a group of
signaling components and can interact simultaneously with
a location within the cell, thereby enabling spatial organi-
zation of signaling pathways. Bidirectional specificity itself
is a general mechanism for routing signals. An example of
this bidirectional behavior is the mechanism of protein
kinase A anchoring that ensures that PKA is exposed to
localized changes in cAMP and is compartmentalized with
e
SCAFFOLDING PROTEINS: SIGNALING
NETWORKS FORM SIGNALING
COMPLEXES
Signaling networks are organized as complexes of signaling
proteins. The organization of these complexes is dynamic
and the complexes can often be assembled in response to
incoming signals by proteins named scaffolding proteins.
One of the best examples of these complexes is postsynaptic
density (PSD), a protein-dense specialization attached to the
synaptic junction in neurons. It lies adjacent to the cyto-
plasmic face of the postsynaptic plasma membrane, in close
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