Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 115

A

Signal initiation
H

H H

E1

Dyn Dyn

β γ

β γ

α

P

GTP

H

P GRK2

“Signalsome”
assembly

A rr
E2

P

P

Early
endosome

Arr

G protein-dependent
signaling

E2

H

A rr
E2

P

P

Arrestin-dependent
signaling

B

G protein-dependent signaling
Second messenger dependent

Arrestin-dependent signaling
Signalsome dependent

Seconds to minutes Minutes to hours

Time range

Figure 5.2 Arrestin scaffolds impose spatial and temporal regulation of signaling path-
ways. (A) Upon agonist (H) binding, GPCRs engage heterotrimeric G proteins, activating
G protein-regulated effectors (E1) at the plasma membrane. Within seconds, GRK phos-
phorylation of the activated receptor creates high-affinity arrestin-binding sites. Arrestin
binding uncouples the receptor from heterotrimeric G proteins while targeting it for
endocytosis. As arrestins translocate to the receptor, they recruit additional catalytically
active proteins (E2) into receptor - arrestin signalsomes. These stoichiometric signaling
complexes transmit a distinct set of signals as the receptor internalizes and transits the
intracellular compartment. (B) G protein-dependent signaling is characterized by rapid
onset followed by waning intensity, reflecting desensitization due to receptor phos-
phorylation by second messenger-dependent protein kinases and GRKs, and arrestin
binding. In contrast, arrestin-mediated signals are of slower onset and often sustained
in duration. (A) Reproduced from Ref. 33 .