The Role of b-Arrestins in Cancer - Progress in Molecular Biology and Translational Science - page 389

the formation of this complex by expression of a dominant negative ARRB
inhibited SP-induced anti-apoptotic effects. 46 Another study demonstrated
that stimulation of various GPCRs ( N -formyl peptide receptor, AT 1 AR,
V 2 R, and CXCR2) was able to initiate apoptosis in ARRB1 and ARRB2
knockout MEFs and restoring expression of ARRBs in these deficient cells
attenuated GPCR-stimulated cell death. 47,48 Studies expressing truncated
versions of ARRB2 in MEFs deficient in both ARRBs found sequences
in the C-terminal tail of ARRB2 that are essential to preventing apoptosis. 7
Interestingly, the binding of ARRB2 alone to the GPCRwas insufficient to
prevent apoptosis in MEFs. Preventing GPCR-mediated apoptosis was
dependent on the interaction between the GPCR-bound ARRB and adap-
tor protein-2. 6,7
The anti-apoptotic properties of ARRBs are the result of its ability to act
as a scaffold following receptor stimulation and subsequently mediate down-
stream anti-apoptotic signals. A recent study showed the apoptotic signaling
promoted by Toll-like receptor 4 following serum deprivation is through
activation of GSK-3

b , and expression of ARRB2 greatly attenuated

activation. 49 A similar study performed in endometrial cancer cells
found that apoptosis induced by resveratrol treatment was negatively regu-
lated by ARRB2 expression by affecting the Akt/GSK-3

GSK-3 b

pathways. 13
ARRB2 has been shown to mediate anti-apoptotic signaling through
MAPK-RSK and PI3K-AKT activation upon stimulation of the angioten-
sin II type 1A (AT 1A ) receptor by phosphorylation of pro-apoptotic protein
BAD. 50 Conversely, one study demonstrated that a nonphosphorylated
form of ARRB2 promoted apoptosis following exposure to UV through
the stabilization of I

b

B nuclear trans-
location, consequently suppressing its anti-apoptotic signaling. 51 The role of
ARRB proteins in apoptosis remains to be fully elucidated, but it is clear that
both ARRB proteins are important in mediating anti-apoptotic signals.

k B a which binds to and prevents NF k

3. THE ROLE OF ARRBs IN CANCER
3.1. Breast cancer
The role of ARRBs in breast cancer is not well understood. Very few studies
have explored the impact of ARRBs in breast cancer cell models. The ear-
liest report indicated that both ARRBs are critical for constitutive PAR-2-
mediated cell migration in the metastatic breast cancer cell line MDA
MB-231. 44 Signaling pathways for the coagulation cascade involving
PAR-2 and tissue factor cytoplasmic domain signaling have been linked