Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 471

arrestin2 and 3 play opposing roles in regulation of vascular smooth muscle
proliferation. In primary vascular smooth muscle, SII induces ERK1/2 acti-
vation and proliferation by promoting AT 1A receptor-dependent EGF
receptor transactivation. 69 Ang II and SII both stimulate Src-dependent
EGF receptor phosphorylation on Tyr 845 , an effect that is lost when arrestin3
is downregulated by RNA interference. 70
Arrestin signaling also promotes cell proliferation in some forms of can-
cer. Human bladder cancer cells express high levels of both the thromboxane
(TP)-

b receptor isoform and arrestin3, and the degree of TP- b upregulation

correlates with poorer prognosis. 71 TP- a and TP- b are splice variants that

differ only in the C-terminus, with TP- carrying a longer tail that allows it

to engage arrestin3 and undergo agonist-dependent

b

internalization. 72

Expressing TP- in nontransformed SV-HUV urothelial cells, confers

agonist-dependent ERK1/2 and FAK phosphorylation, and enhances cell
proliferation, migration, and invasion in vitro , responses that are lost when
arrestin3, but not arrestin2, is downregulated by RNA inference. Similarly,
arrestin2-dependent activation of c-Src and EGF receptor appears to con-
tribute to the tumor promoting effects of Prostaglandin E (EP)2 receptors
in papilloma formation. 73 In non-small cell lung cancer, arrestin2 mediates
nicotine-induced epithelial cell proliferation through activation of the
MAPK and Rb-Raf-1 pathways. 65

b

4.3. Non-proliferative cell growth
Some evidence suggests that control of non-proliferative cell growth,
that is, hypertrophy, may be a conserved arrestin-dependent signaling func-
tion. Arrestin scaffolding of the ERK1/2 cascade allows it to preferentially
target membrane and cytosolic substrates including the ribosomal S6 ki-
nase, p90RSK, 43 and MAP kinase-interacting kinase 1 (Mnk1), a regulator
of the ribosomal protein translation initiation complex. Arrestin3-dependent
ERK1/2 activation by the AT 1A receptor mediates phosphorylation of
Mnk1 and eukaryotic translation initiation factor 4E (eIF4E), increasing
rates of mRNA translation. 74 In addition, arrestin scaffolding of the
PP2A-AKT-GSK3 complex may permit GPCR crosstalk with PI3K-AKT
regulation of mammalian target of rapamycin (mTOR), a critical coordinator
of the nutrient-sensing and cellular growth responses. 40
In vitro , a mutant angiotensin AT 1A receptor with a deletion in its second
intracellular loop that inhibits G protein coupling (AT 1 -i2m) activates an
Src-Ras-ERK1/2 pathway leading to cytosolic ERK1/2 and p90RSK