Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 422

functionality. 63,64 This preorganization of signaling proteins allows for the
faithful transmission, without signal dilution or disruption, of the GPCR
stimulus to the correct intracellular microdomain. The molecular integra-
tion and organization of distinct multiple signals emanating from discrete
GPCRs likely occurs at the level of the structured assembly and interaction
of their associated signal transduction proteins. Multiple coherently associ-
ated components of these signaling cascades have been shown to be pre-
assembled into higher order structures by molecular scaffolding proteins,
including POSH (protein kinase A anchoring protein), 65 POSH (plenty
of SH3 domains), 66 JIP (c-Jun amino-terminal kinase-interacting protein), 67
14-3-3 proteins, 68 and perhaps most importantly b -arrestins. 69 These inte-
grating proteins compartmentalize signaling pathways in the cell, enhance
specificity of target-substrate interactions, and improve the speed and effi-
ciency of signal transduction. Thus, there is a channeling of the complex and
diverse signaling inputs from ligands and their specific target GPCRs at the
plasma membrane into higher order multiprotein signaling scaffolds,
attached either to cytoskeletal proteins or the plasma membrane itself.
The enormous diversity of GPCR-ligand interactions, coupled with a com-
plex series of potential signaling scaffolds, allows specific GPCR signaling
patterns at the plasma membrane surface to be functionally encrypted in a
myriad of combinations to ensure faithful transmission of virtually any type
of initial stimulus. Many cell surface receptors utilize the same types of sig-
naling proteins, so, therefore, the intrinsic individual nature of those down-
stream signaling molecules cannot be specific enough to solely encrypt the
unique signaling “information” of the specific stimulating ligand-receptor
interaction. However, a simple and unique stoichiometric combination of
common downstream signaling proteins would allow the generation of a
virtually limitless number of encryptons (multiprotein signaling quanta), all
able to convey information from a wide range of inputs that impinge upon
the cell in a plethora of combinations, temporal sequences, and concentra-
tions. The enormous functional diversity of GPCR signaling traffic is, there-
fore, facilitated and mediated through the connection between the ligand-
bound receptors and the complex signaling quanta (encryptons). These
encryptons are likely to be composed of multiple signaling molecules along
with their associated scaffold and trafficking proteins. 70,71 These functional
microcomplexes, therefore, assemble in a manner that allows the functional
encryption of the exact qualitative and quantitative nature of the initial input
ligands. The effective clustering of signaling molecules into multiprotein sig-
naling complexes eliminates delays that would otherwise occur as a result of