Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 125

myocardial apoptosis. In this model, inhibiting EGF receptors worsens the
dilated cardiomyopathy, suggesting a protective role for transactivated EGF
receptors in the heart. 62
Arrestin signaling is not the only mechanism of GPCR-stimulated
ectodomain shedding, and, in some cases, arrestin-mediated GPCR desen-
sitization antagonizes signaling by transactivated EGF receptors.
In arrestin2/3 null MEFs, ERK1/2 activation by LPA receptors reflects pri-
marily G protein-dependent transactivation of EGF receptors. 64 Because
LPA receptor desensitization is impaired, the EGF receptor-dependent
ERK1/2 signal is persistent, lasting for several hours in the continued pres-
ence of LPA. Reintroducing arrestin3, which restores desensitization, makes
the transactivation-dependent signal transient, such that it contributes
significantly to ERK1/2 activation only during the first fewminutes of stim-
ulation. At the same time, arrestin3 confers a long-lasting EGF receptor-
independent ERK1/2 signal that presumably reflects activation of the
arrestin-scaffolding pathway. Whereas most of the early LPA-stimulated
transcriptional responses in arrestin2/3 null MEFs are EGF receptor-
dependent, expression of arrestin3 attenuates EGF receptor-dependent tran-
scription and enables LPA to elicit EGF receptor-independent transcription.
4.2. Mitogen-activated protein kinases
4.2.1 Extracellular signal-regulated kinases
ERK1/2 activity is required for G0-G1 cell-cycle transition and the passage
of cells through mitosis or meiosis. 82 Heptahelical receptors employ multiple
mechanisms to activate ERK1/2, often simultaneously, from PKA- and
PKC-dependent signals downstream of heterotrimeric G proteins, to trans-
activation of EGF receptors, to signals transmitted via arrestins. 81,83 As a
result, GPCR-mediated ERK1/2 activation in any given setting is complex,
as are the functional consequences. Regarding arrestin-dependent ERK1/2
activation, several factors influence the spatial distribution and duration of
ERK1/2 activity including the specific GRK and arrestin isoforms acting
on the receptor, and the stability of the receptor-arrestin interaction.
Although arrestins 1, 2, and 3, but not arrestin4, are able to bind ERK1/
2, 84 evidence suggests that, at least with some receptors, the arrestin2 and 3
isoforms play opposing roles in arrestin-mediated signaling and desensitiza-
tion. In HEK293 cells expressing AT 1A receptors, isoform-selective down-
regulation of endogenous arrestin3 reduces angiotensin II-stimulated
ERK1/2 activation by about 50% and abrogates activation the arrestin
pathway-selective ligand SII. Paradoxically, silencing arrestin2 expression