The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 388

Recent studies have demonstrated the importance of ARRBs inmigration
and invasion of various types of cancers. In transgenic mice, overexpressing
HA-tagged ARRB1 increased vascular endothelial growth factor (VEGF)
expression, MMP9 activity, and overall growth, and decreased tumor initia-
tion time when subcutaneously injected with tumor cells. 41 The lipid medi-
ator lysophosphatidic acid (LPA) receptor is a GPCR that associates with
ARRB proteins to mediate tumor cell invasion and migration, and both
are found overexpressed in advanced stages of breast cancer. 42 Breast carci-
noma cells under hypoxic conditions expressed elevated levels of vascular
endothelial growth factor-A (VEGF-A) as a result of stabilization of its tran-
scriptional regulator HIF-1 by

ARRB1 in the nucleus was essential for mediating VEGF cell survival signals
in hypoxic conditions. 43 Another study in breast cancer cells demonstrated
that protease-activated receptor-2 (PAR-2) requires the recruitment and scaf-
folding of both ARRB proteins to activate ERK1/2 and promote tumor cell
migration. 44 Further studies determined that PAR-2 stimulation resulted in
ARRB1 binding to PI3K, which inhibited its activity. 45 In colorectal cancer,
ARRB1 is necessary for the formation of a signaling complex facilitating in
the interaction of the PGE 2 receptor with c-Src, resulting in transactivation
of the EGF receptor and downstreamAkt signaling. 5 Blocking the interaction
between ARRB1 and c-Src decreased migration and invasiveness of colorec-
tal carcinoma cells, as well as the number of metastatic liver lesions in vivo. 5
In ovarian cancer cells, the interaction between ARRB and c-Src following
endothelin-A receptor stimulation was found to be crucial for EGF receptor
transactivation,

a by ARRB1. This stabilization of HIF-1 a

inactivation of glycogen synthase kinase-3 b (GSK-3 b ),

-catenin signaling pathways. 4 Similar to colorectal
carcinoma metastases, ovarian cancer cells that expressed a mutated ARRB1
protein that prevented its interaction with c-Src exhibited a reduced
metastatic rate. 4 Thus, the scaffolding ability of the ARRB proteins appears
to determine its involvement in invasion and migration of normal and
malignant cells.

and activation of the b

2.3. Apoptosis and survival
A novel role of ARRBs has been identified in regulating GPCR-mediated
apoptosis. The first study demonstrated that the anti-apoptotic effects of the
neuropeptide substance P (SP) on neurokinin-1 receptor (NK1R)
expressing endothelial cells involved ERK1/2 activation following forma-
tion of a complex consisting of NK1R-ARRB-Src-ERK. Disrupting