Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 130

rearrangement of actin bundles. Activation of PAF receptors leads to recruit-
ment and activation of an arrestin2-ASK1-MKK3-p38 MAPK signalsome,
which is required for subsequent cell polarization, actin bundle formation,
and receptor endocytosis. 97 While the antiapoptotic effects of arrestins are
mediated primarily through activation of the prosurvival kinase AKT
( vide infra ), such that genetic deletion of either arrestin increases apoptosis
after serumwithdrawal, deletion of both arrestin2 and 3 is paradoxically pro-
tective. 98 Individual deletion of either arrestin2 or 3 enhances starvation-
induced activation of ERK1/2 and p38MAPK and caspase 3 cleavage, while
decreasing AKT activity. When both are deleted, starvation-induced
ERK1/2 and p38 MAPK activation returns to wild-type levels. This sug-
gests that both arrestins are required to maintain a balance between
proapoptotic p38 MAPK and antiapoptotic AKT-signaling pathways.

4.3. Other SER/THR kinases
4.3.1 Regulators of nuclear factor- B

As previously discussed, arrestins2 and 3 appear to act as negative regulators
of NF- k B transcription by sequestering the NF- k B inhibitor, I k B a , and
protecting it fromphosphorylation by I k B a kinases, which promotes its deg-
radation. b 2-Adrenergic receptor stimulation increases arrestin3 binding to
I k B a , preventing its phosphorylation-dependent degradation and inhibiting
IL-8-stimulated NF- k B activity. 54,55 Consistent with this, TLR4-mediated
activation of an NF- k B reporter is enhanced by downregulating arrestin
expression. 56 Arrestin binding to the E3 ubiquitin ligase, TRAF6, probably
augments the inhibition of TLR signaling. 99 TRAF6 is normally recruited
to TLR/IL-1 family receptors where it facilitates I k B kinase and NF- k B
activation. Binding of TRAF6 to arrestin2 and 3 in response to lipopolysac-
charide or IL-1 stimulation prevents TRAF6 oligomerization and
autoubiquitination, negatively regulating LPS and IL-1 signaling.
The capacity to negatively regulate NF- k B transcriptional pathways
involved in cytokine signaling suggests that arrestins may dampen immune
responses by inhibiting the production of proinflammatory cytokines. Con-
sistent with this, isolated peritoneal neutrophils from arrestin3 null animals
exhibit increased basal and LPS-stimulated TNF a and IL-6 production. 100
Arrestin effects in cancer may also derive in part frommodulation of NF- k B
signaling. Loss of expression of the type III transforming growth factor- b
(T b RIII) occurs in a variety of human malignancies. T b RIII is thought
to function as a tumor suppressor by reducing cell motility. Although not
a GPCR, clathrin-dependent endocytosis of T b RIII and downregulation

k