Systems Analysis of Arrestin Pathway Functions - Progress in Molecular Biology and Translational Science - page 421

factor receptor kinase. 47,48 In addition to linking kinase systems to GPCRs,
b -arrestins can facilitate the receptor-mediated cellular localization of solute
carriers (Slc24a/GLUT4 49 ) as well as play a vital role in chemotactic 50-52 and
apoptotic 53-55 mechanisms. Along with these multiple “intermediary
metabolic” actions of GPCR-mediated b -arrestin signaling, recent evidence
has also demonstrated that b -arrestin signaling engenders strong transcrip-
tional and translational signaling behavior. 26,56-59 While considerable infor-
mation concerning the existence of distinctive b -arrestin signaling modalities
now exists, further and more nuanced investigation of this new signaling par-
adigm are required. Such a “next-level” analytical investigation is required,
as a large percentage of the current analysis has been performed using in vitro
cell systems and global congenital b -arrestin knock-out mouse models. The
latter murine knock-out mice for b -arrestins are likely to provide GPCR
signaling data that are highly skewed, as loss of this vital molecule will impact
an enormous range of collateral physiological processes. The ability to dissect
specific b -arrestin signaling functionalities from knock-out mice becomes
more and more unlikely as we begin to better appreciate the multiple and
often paradoxical effects 60,61 upon protein and gene function that genomic
ablation of vital keystone factors such as b -arrestin can engender. It is the mul-
tidimensional functional capacity of b -arrestins to condition multiple forms
of GPCR signaling that makes their biological role so important. We shall
discuss the role of such keystone molecules in signal integration and encryp-
tion in the following section.
2.3. Signal integration and encryption
It can be simply considered that the primary role of GPCRs is to facilitate
transmembrane cellular signal transduction for extracellular ligands of all
varieties. While the relationship between stimulating ligand and recipient
GPCR is considered tight and specific, the nature of the downstream
GPCR-associated signaling pathways is in contrast thought to be generic
and highly flexible. For cells to allow the discrete transmission of specific
ligand-based signaling information to the cell interior, the functional mes-
sage needs to be efficiently encrypted at the signal transduction level. 62 Intra-
cellular signaling pathways were initially thought to consist of linear and
isolated proteins such as kinases, adapters, and subsequent targets. Evidence
gathered over recent years has uncovered the fact that signaling pathways can
be highly branched, and transduction modules formerly thought to operate
independently participate in a substantial degree of preorganized signaling