The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 385

the breast, lung, prostate, brain, and hematologic system. Collectively, these data build a
strong case that ARRB-dependent signaling contributes to the cancer phenotype and
that the ARRBs may represent novel therapeutic targets in certain malignancies.

1. INTRODUCTION
The nonvisual arrestins, -arrestin (ARRB) 1 and 2, play important

roles in regulating cellular signaling processes including several that alter cell
phenotype and lead to the progression of cancer. ARRBs were initially
reported to mediate desensitization of G protein-coupled receptor
(GPCR) signaling by regulating receptor internalization. 1 Subsequently,
major progress in our understanding of ARRB function has revealed addi-
tional roles in cell signal regulation as ARRBs have been shown to scaffold
proteins within the cytoplasm and translocate to the nucleus to regulate sev-
eral cellular processes. 2 ARRB-regulated cellular processes are commonly
associated with cancer cell phenotypes such as cell proliferation, 3 cancer cell
migration, invasion, and metastasis. 4,5 Recent advances have further impli-
cated ARRB in novel roles related to cancer progression, including the inhi-
bition of cell death, activation of tyrosine kinase pathways, and the
regulation of gene transcription. ARRBs have a role in the regulation of cel-
lular apoptosis demonstrated in a variety of cancer and noncancerous cell
lines, contributing to uncontrolled growth. 6-14 Extracellular signal-
regulated kinase (ERK) signaling can also contribute to abnormal cell pro-
liferation and cancer progression. ARRBs mediate ERK1/2 activation both
directly and indirectly via interaction with the cellular proto-oncogene
c-SRC. 15 ARRBs can also directly interact with c-SRC and promote
migration and invasion independent of ERK1/2. Furthermore, malignant
cells often take hostage of GPCRs to migrate and invade into surrounding
tissues. ARRBs facilitate this process by recruiting a large number of other
nonreceptor tyrosine kinases to various GPCRs. 16 The role of ARRBs in
regulating gene transcription was first described in 2001; ARRB1 regulated
the activation of the lymphoid enhancer transcription factor through its
interaction with phosphorylated dishevelled 1 and 2. 17 Following nuclear
translocation, ARRB1 is able to interact with histone acetyltransferase
p300 and cAMP response element-binding protein to regulate histone acet-
ylation and gene transcription. 18
Major advances in our understanding of the molecular mechanisms of
ARRB signaling over the past decade have been made possible by an

b