Arrestins and Protein Ubiquitination - Progress in Molecular Biology and Translational Science - page 178

Class A trafficking

Agonist

β 2 AR

P

P P P

P P P P Internalization

β -Arrestin

P

Mdm2

Transient
ubiquitination

Transient
pERK

Endosome

C-Raf ERK

MEK

β -Arrestin

B

Class B trafficking

Agonist

AT 1a R
V 2 R

P P P P

P P Internalization

P P

-Arrestin

P

E3 ligase?

Stable
ubiquitination

Sustained pERK;
formation of
signalsomes

Endosome

P
P

P

Figure 7.3 Ubiquitination and trafficking profiles of b-arrestin2. Agonist stimulation of
7TMRs leads to rapid phosphorylation of the receptor by GRKs. Phosphorylated recep-
tors recruit the cytosolic adaptor protein b-arrestin. Most 7TMRs are capable of rec-
ruiting b-arrestin. However, the nature of b-arrestin/7TMR complexes can be
transient (class A receptors) or stable (class B receptors). (A) Activation of the class
A b 2 adrenergic receptor (b 2 AR) induces rapid and transient ubiquitination of b-arrestin
by an E3 ubiquitin ligase, Mdm2. The ubiquitinated b-arrestin - receptor complex
engages an ERK-signaling scaffold at the plasma membrane and enhances transient
phosphorylation of ERK. The ubiquitinated b-arrestins are rapidly deubiquitinated
and dissociated from the internalizing receptor, while 7TMRs are internalized into
endocytic vesicles. (B) Activation of class B receptors induces sustained b-arrestin
ubiquitination by an unknown E3 ligase, leading to the formation of stable endocytic
complexes. These stable complexes are localized to perinuclear endosomal compart-
ments and ERK phosphorylation is sustained on signalsomes (signaling endosomes).