Biology Reference
In-Depth Information
activation was published over a decade ago by Pierce et al. 33 Several studies
confirmed the role of ARRBs in the regulation of cellular proliferation
through their interaction with both G protein-dependent and
-independent signaling pathways. 34 ARRB signaling has been shown to
regulate the activity of PI3K following stimulation of the insulin-like
growth factor type 1 (IGF-1) receptor tyrosine kinase. 11 In non-small-cell
lung cancer (NSCLC), ARRB1 has been shown to regulate nicotine-
induced epithelial cell proliferation by activating Src and Rb-Raf-1
pathways. The binding of the nicotine to nicotinic acetylcholine receptors
(nAChRs) causes the recruitment of ARRBs and Src and results in the
activation of the MAPK and Rb-Raf-1 pathways. These events subse-
quently cause the recruitment of E2F1, Rb, and Raf-1 to E2F-responsive
proliferative promoters. The inactivation of Rb by Raf-1 facilitates the dis-
sociation of Rb from the promoters, which combined with the increased
binding of E2F1, causes transcription of S-phase genes and cell cycle pro-
gression. Ablation of ARRBs using RNA interference blocked nicotine-
induced proliferation of NSCLCs, blocked activation of Src, suppressed
levels of phosphorylated ERK, and abrogated Rb-Raf-1 binding in
response to nicotine. 35
2.2. Cell migration and invasion
The ARRB proteins play a significant role in mediating signals for
cell migration and invasion of normal and malignant cells. The role of
ARRBs in regulating cell migration was first demonstrated in a study
that found impaired CXCR-mediated cell motility in the lymphocytes
obtained from ARRB2 knockout mice, compared to their wild-type
litter mates. 36 Additional studies found that the CXCR-mediated cell
migration was ARRB dependent, resulting in increased activation of
p38, MAPK, SAPK, and ERK1/2 pathways. 37 Knocking down ARRB
expression with siRNA or introduction of a dominant negative
ARRB attenuated the increased migration and associated signaling. 37
Suppression of ARRB2 was associated with decreased stromal cell-derived
factor 1
-induced cell migration via decreased p38 MAPK activation in
HEK293 cells. 38 The IGF-1 receptor is involved in the cell cycle regula-
tion of normal and malignant cells. 39 Stimulation of the IGF-1 receptor
causes it to associate with ARRB1 resulting in both the formation of
a complex with Mdm2,
a
leading to its proteosomal destruction, and
ERK1/2 activation. 40
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