Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 129

physiologic animal model of cerebral ischemia, the angiotensin receptor
blocker, losartan, has been reported to attenuate neuronal damage by
inhibiting the assembly of an AT 1A receptor-arrestin3-Ask1-MKK4-
signaling module and repressing the activation of JNK3, c-jun, and

caspase-3, and the release of cytochrome C. 95

4.2.3 p38 MAP kinase
Although the molecular mechanisms of activation have not been character-
ized in any detail, several studies have reported arrestin-dependent regulation
of the p38MAPkinase cascade. InHeLa andHEK293 cells, overexpressionof
arrestin3 enhanced, and downregulation inhibited, activation of both p38
MAPK and ERK1/2 following stimulation of the chemokine receptor
CXCR4 by its ligand, stromal cell-derived factor 1 a . 65 Inhibiting p38
MAPK, but not ERK1/2, blocked arrestin3-dependent chemotaxis,
suggesting a specific role for arrestin-dependent p38 MAPK in CXCR4
signaling. In primary cultured astrocytes, k -opioid receptor-stimulated
activation of p38 MAPK appears to involve GRK3 and arrestin3. 66 p38
activation does not occur in astrocytes derived from k -opioid receptor or
GRK3 null mice, or following downregulation of arrestin3 expression.
As with ERK1/2, however, the dominant effect of arrestins in other sys-
tems appears to attenuate p38 MAPK activation via G protein-dependent
pathways. Arrestin2/3 null MEFs exhibit greatly enhanced activation of
ERK1/2, JNK1/2, and p38MAPK in response to the CXCR2 agonist, inter-
leukin 8. 67 Activation of the stress kinases, JNK1/2 and p38 MAPK, was
dependent on reactive oxygen species generated by NADPH oxidase, and
arrestin expression conferred protection from oxidative burst-induced cell
death resulting from sustained CXCR2 activation. Similarly, b 2-adrenergic
receptor-mediated regulation of immunoglobulin IgE expression on
CD40L/interleukin-4-activated B lymphocytes involves PKA and p38
MAPK, but not arrestins. b 2-Adrenergic receptor stimulation leads to
Gs/cAMP/PKA-dependent phosphorylation and inactivation of the hemato-
poietic protein tyrosine phosphatase, HePTP, which releases bound p38
MAPK, making more available for phosphorylation and subsequent IgE
regulation. 96 In this setting, arrestin-dependent b 2-adrenergic receptor desen-
sitization would attenuate, not enhance p38 MAPK activity.
Besides CXCR4-mediated chemotaxis, 65 arrestin-dependent regulation
of p38 MAPK has been implicated in several cellular processes.
In polymorphonuclear neutrophils, clathrin-mediated endocytosis of the
platelet-activating

receptor (PAF) requires p38 MAPK-dependent