Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 112

of the extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal
kinase (JNK)3 mitogen-activated protein kinase (MAPK) cascades 13-15 ; the
E3 ubiquitin ligase; Mdm2 16 ; the cAMP phosphodiesterases, PDE4D3/5 17 ;
diacylglycerol kinase (DGK) 18 ; the inhibitor of nuclear factor- k B, I k B a

19

;
the Ral-GDP dissociation stimulator, Ral-GDS 20 ; the actin filament-
severing protein, cofilin 21 ; and the Ser/Thr protein phosphatase 2A
(PP2A). 22,23 Indeed, the signaling repertoire accessible to GPCRs through
arrestin “coupling” may be as diverse as that mediated by heterotrimeric
G -protein-regulated effectors ( Fig. 5.1 ). Moreover, since arrestins uncouple

H

G protein
signaling network

Arrestin
signaling network

GRK

Arr1/4 Arr2 Arr3

Gs Gi/o Gq/11 G12/13

Desensitization

G α
β

G α
β

G α
β

G α
β

Arr

γ γ γ γ Arr Arr

I κ B α
I κ K α

Cofilin
Chronofin

AC
PKA

GIRK PLC β Rho-GEF Src Raf

MEK
ERK

PDE4D DAGK PP2A

AKT
GSK3

PKC

Mdm2 Ral-GDS

LIMK

Figure 5.1 Pluridimensional GPCR-signaling networks. Agonist binding to a GPCR stim-
ulates the intrinsic guanine nucleotide exchange factor activity of the receptor, activat-
ing heterotrimeric G proteins and initiating second messenger-dependent pathways,
including Gs-adenylyl cyclase (AC) - PKA and phospholipase Cb (PLCb) - PKC. Numerous
other effectors, including gated inwardly rectifying K þ channels (GIRK) and small
GTPases like Rho-guanine nucleotide exchange factor (Rho-GEF) are regulated by acti-
vated Ga or Gbg subunits. Agonist-occupied GPCRs are phosphorylated by GRKs, pro-
moting arrestin binding. Arrestins uncouple the receptor and G protein, leading to
desensitization of G protein signaling and internalization of the receptor. Arrestins also
function as ligand-regulated scaffolds, recruiting catalytic proteins to initiate a second
wave of signaling events. Arrestin-coupled effectors include Src family tyrosine kinases
(Src), E3 ubiquitin ligases (Mdm2), components of the ERK1/2 mitogen-activated protein
kinase cascade (Raf - MEK - ERK1/2), cAMP phosphodiesterases (PDE4D), the Ral-GDP dis-
sociation stimulator (Ral-GDS), diacylglycerol kinases (DAGK), regulators of nuclear
factor-kB signaling (IkBa - IkKa), the glycogen synthase kinase 3 regulatory complex
(PP2A LIMK).

Evidence suggests that the signaling network mediated by arrestins may rival the
G protein-signaling network in diversity. Reproduced from Ref. 24 .

Akt GSK3), and the actin filament-severing complex (cofilin chronofin

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