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G protein-dependent and arrestin-dependent signals, supporting the con-
cept that these two networks regulate largely distinct subsets of downstream
effectors. The arrestin-dependent kinase network included several kinases
previously reported to be regulated by G protein-independent mechanisms,
including A-Raf, Rsk-1, p70S6 kinase, and calmodulin-dependent protein
kinase 2, and also pointed to protein kinase D as a downstream target of
arrestin signaling.
3. POSITIVE AND NEGATIVE REGULATION OF KINASE
PATHWAYS
The duality of arrestin function that characterizes its actions with
respect to G protein-mediated and arrestin-mediated signaling processes
has curious parallels in its kinase and phosphatase scaffolding role. The bind-
ing of pathway components to arrestins not only facilitates ligand-dependent
arrestin signaling but also allows arrestins to sequester kinases and regulatory
proteins in a manner that dampens basal pathway activity.
3.1. Negative regulation of second messenger-dependent
protein kinases
The simplest negative regulatory role of arrestin scaffolds is one that com-
plements its roles in GPCR desensitization and sequestration. Two enzymes
involved in second messenger breakdown have been reported to bind
arrestins: type 4D cAMP phosphodiesterases (PDE4D) and DGK.
Arrestin-dependent recruitment of these enzymes to the locus of second
messenger production serves as an additional means of limiting the magni-
tude and duration of G protein-mediated activation of the second
messenger-dependent protein kinases, protein kinase (PK)A and PKC.
Arrestins 2 and 3 interact with all five PDE4D isoforms, PDE4D1-5. 17
The Gs-coupled b 2-adrenergic receptor forms a signaling complex with
arrestin3 and PDE4D3 and PDE4D5, leading to accelerated cAMP degra-
dation. Recruitment of PDE4D into the signalsome appears to be highly
receptor specific, since the closely related b 1-adrenergic receptor was shown
to recruit a different alternative-spliced isoform, PDE4D8, and to do so
without the aid of arrestin. 53 Arrestin-dependent recruitment of DGK
appears to dampen M1 muscarinic receptor-mediated PKC activity. 18
DGK converts diacylglycerol produced by PLC b to phosphatidic acid.
Besides
terminating PKC activity,
this mechanism may generate
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