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random signaling protein diffusion in the cytoplasmic space. In addition, as
many cellular stimuli are likely to simultaneously impinge upon cells, rather
than individually as in most contrived
in vitro
cellular experiments, this form
of signaling architecture organization is crucial for eliciting the appropriate
physiological response during such times of multiple ligand input. Organiz-
ing an efficient and discrete signaling architecture requires the accurate
selection of effector molecules for regulated activation and deactivation,
often by phosphorylation and dephosphorylation events. A principal strategy
in achieving this selection specificity is compartmentalization of signaling
enzymes and trafficking adapters.
72
As we have previously discussed,
b
-arrestin molecules appear to play a multidimensional role in organizing
the interaction and clustering of multiple enzymes, their effectors, and their
associated targets. In addition to the multiple kinase systems that are rec-
ruited to GPCRs via
b
-arrestin,
b
-arrestins are also able to orchestrate the
creation of signaling
encryptons
including diverse enzymes such as
c-Raf,
73,74
c-Jun N-terminal kinase 3,
75
apoptosis signal regulating kinase
1,
76
phosphodiesterase 4D5,
77
the E3 ubiquitin ligase transformed mouse
3T3 cell double minute 2,
78
cAMP-regulated guanine nucleotide exchange
factor I,
79
and LIM domain-containing protein kinase.
80
Therefore, as
b
-arrestins possess both the ability to interact with multiple cell surface
GPCRs as well as a huge variety of signaling enzymes and subcellular
targeting adapters, one could easily consider that
b
-arrestins must constitute
one of the most important signaling traffic mediators and
encrypton
compo-
nents. The near ubiquitous nature of
b
-arrestin expression, therefore, may
represent one of the universal mechanisms for GPCR signal conditioning
and regulation.
b
-arrestins are therefore likely to regulate the temporal
and spatial signal encryption of the original GPCRs functional input.
An understanding of how multiple inputs are integrated, or differentiated,
by
b
-arrestin-based
encrypton
complexes will likely provide a better appreci-
ation of how GPCRs mediate intracellular signaling events in real physio-
logical settings. A more in-depth understanding of
b
-arrestin-conditioned
GPCR signaling thus may facilitate the discovery of
b
-arrestin signaling-
biased GPCR ligands. We shall consider in later sections how the molecular
investigation of encrypton structure may aid this drug discovery process.
3. SYSTEMS ANALYSIS OF RECEPTOR SIGNALING
SYSTEMS
The field of GPCR signal transduction over the past decade has begun
to efficiently and productively interact with the mass data analytical realms of
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