Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 127

translocation and stimulates proliferation. Similarly, the wild-type AT 1A
receptor activates ERK1/2 using both G protein- and arrestin-dependent
pathways, increasing both cytosolic and nuclear ERK1/2, 25,34 whereas a
G protein-uncoupled DRY-AAY AT 1A receptor mutant, which utilizes
only the arrestin pathway, only activates cytosolic ERK1/2 and fails to elicit
a detectable transcriptional response. 46 Native V2 receptors similarly engage
both pathways. Exchanging the V2 receptor C-terminus for that of the Class
A b 2-adrenergic receptor, which converts the receptor from stable to tran-
sient arrestin binding, increases the proportion of ERK1/2 that enters the
cell nucleus and permits the chimeric receptor to stimulate cell proliferation.
The opposite effect is obtained when the V2 receptor tail is appended to the
b 2 receptor. 31
Whether ERK1/2 activated by Class A receptors using the arrestin path-
way is transcriptionally competent is less clear. Class A receptors, like the b 2-
adrenergic and LPA receptors, also use arrestin scaffolds to activate ERK1/2,
but the transient nature of the receptor-arrestin interaction does not support
endosomal targeting. 64,85 Reintroduction of arrestin3 into arrestin2/3 dou-
ble null MEFs restores arrestin-dependent ERK1/2 activation, and while it
represses transcription mediated through G protein-dependent trans-
activation of EGF receptors, it enables LPA to elicit ERK1/2 dependent,
but EGF receptor-independent transcription. 64 Such findings suggest that
dissociation of the LPA receptor-arrestin complex upon internalization
may permit ERK1/2 activated by the arrestin pathway to enter the cell
nucleus.
The spatial constraint imposed by the assembly of stable signalsomes
appears to direct ERK1/2 kinase activity toward membrane or cytosolic
substrates. ERK1/2 phosphorylates Ser 412 in the C-terminus of arrestin2,
limiting its ability to bind clathrin. 47 Arrestin2 in the cytosol is almost stoi-
chiometrically phosphorylated on Ser 412 , and dephosphorylation of Ser 412
upon receptor binding promotes receptor internalization and ERK1/2 acti-
vation. Rephosphorylation by ERK1/2 in the signalsome complex probably
provides either negative feedback regulation of receptor endocytosis or facil-
itates receptor internalization by promoting dissociation of arrestin and
clathrin, allowing the receptor to exit clathrin-coated vesicles. Arrestin-
dependent targeting of ERK1/2 to the plasma membrane also appears to
play a role in chemotaxis. During PAR2-induced chemotaxis, PAR2
receptor-arrestin-ERK1/2 complexes localize to the leading edge of the
cell where ERK1/2 activity is required for actin cytoskeletal reorganiza-
tion. 49 Other cytosolic ERK1/2 substrates include the ribosomal S6 kinase,