Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 128

p90RSK. ERK1/2 phosphorylation of p90RSK is activated by a mutant
AT 1A receptor with a deletion in its second intracellular loop that inhibits
G protein coupling. 63 This arrestin-dependent activation of the ERK1/2
substrate p90RSK acts in concert with another arrestin-mediated signal,
phosphatidylinositol 3-kinase (PI3K)-AKT to downregulate phospho-
BAD, inducing antiapoptotic cytoprotective effects in rat vascular smooth
muscle. 91 Using RNA interference to downregulate arrestin3, it has also
been possible to show that arrestin-dependent ERK1/2 activation by the
AT 1A receptor mediates phosphorylation of Mnk1 and eIF4E, increasing
rates of mRNA translation. 35

4.2.2 c-Jun N-terminal kinase 3
JNK1-3 are stress-activated kinases that regulate apoptosis by stimulating
cytochrome C release from the mitochondria during cellular stress and con-
trol transcription by phosphorylating the transcription factor c-Jun. 92 There
are three JNK isoforms, of which JNK1/2 are widely expressed, while JNK3
is highly expressed only in brain, heart, and testes. 93 JNK2 and JNK3 were
originally found to interact with arrestin3 in yeast two-hybrid screens, but
only JNK3 interacts with arrestins in mammalian cells. 13 The three compo-
nents of the JNK3 cascade, Ask1, MKK4, and JNK3, are able to bind all four
arrestin isoforms. While all four arrestins can cause JNK3 to redistribute
from its normal nuclear location into the cytosol, only arrestin3 is able to
potentiate JNK3 activation. 36,42
It is unclear whether GPCRs exert any control over arrestin3-dependent
activation of JNK3 or indeed whether activation of arrestin3-JNK3 has a
physiologic role. 94 Interestingly, JNK3 exhibits higher affinity for the
“inactive” conformation of arrestins, suggesting that its dominant role is
to repress basal JNK3 signaling. 36,42 Even though the JNK3 bound to
arrestin3 is active, it is sequestered in the cytosol away from its nuclear tran-
scription factor targets. The original study, performed in transfected cells,
reported that stimulation of AT 1A receptors activated JNK3 and caused it
to colocalize with arrestin3 in endosomal vesicles, 13 but later work per-
formed with the b 2-adrenergic receptor found no evidence of receptor-
mediated JNK3 activation under conditions where ERK1/2 was being
robustly activated via the arrestin3 pathway. To the contrary, expression
of inactive arrestin3 mutants that do not bind GPCRs increased basal
JNK3 phosphorylation while simultaneously decreasing receptor-catalyzed
ERK1/2 activation, confirming that while arrestin3-dependent ERK1/2
activation is receptor dependent, JNK3 activation is not. 30 In a more