Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 474

arrestin3 is downregulated. 71 Similarly, the LPA1 and LPA2
lysophosphatidic acid receptors, arrestins 2 and 3, Ral and Ral-GDS are
all upregulated in more advanced stages of human breast cancer. In vitro ,
LPA stimulates the migration and invasion of MDA-MB-231 breast cancer
cells, and downregulating arrestin or Ral expression inhibits the response. 90
Endothelin ET-A receptors are expressed in a majority of human ovarian
cancers and its co-expression with arrestin2 increases with advancing tumor
grade. In a tumor xenograft model, ovarian cancer cells expressing the
arrestin2 S412D mutant, which impairs arrestin-dependent ET-A receptor
signaling, develop fewer metastases, suggesting that arrestin signaling con-
tributes to ovarian tumor progression and metastatic potential. 91
Seemingly opposing arrestin-dependent regulation of chemotaxis and
production of inflammatory cytokines leads to complex effects in the
immune system. During the immune response, arrestin scaffolding appears
to be required for the establishment of cell polarity and to facilitate degran-
ulation at the site of injury. Splenocytes derived from arrestin3-null mice
exhibit strikingly impaired chemotactic responses to stromal cell-derived
factor-1, CXCL12. 92 Similar observations apply to other GPCRs expressed
in leukocytes, including CXCR1 (IL-8) receptors in RBL cells, 93 CXCR2
(IL-8) receptors in neutrophils, 94 and CXCR3 (CCL-9 and CCL-10),
CXCR4 (stromal cell-derived factor 1

a

), and CCR5 (RANTES) receptors
expressed in HEK293 cells. 95-97 On the other hand, arrestins function as
negative regulators of NF k B signaling, 98-100 and can limit the intensity of
the chemotactic stimulus itself by inhibiting the local production of pro-
inflammatory cytokines. Thus, isolated peritoneal neutrophils from arrestin3
null animals exhibit increased basal and LPS-stimulated TNF a and IL-6

production. 101
Which of these potentially opposing functions of arrestins dominates
in vivo appears to vary. In allergen-sensitized arrestin3-null mice, T helper
(Th)2 cell chemotaxis into the lungs is blunted and levels of the
Th-derived cytokines IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid
are markedly reduced, suggesting that impaired chemotaxis leads to a dimin-
ished immune response. 102 In contrast, an in vivo study of CXCR2-mediated
chemotaxis found that neutrophil recruitment to sites of inflammation in both
a dorsal air pouch and an excisional wound model was increased in arrestin3
null mice despite impaired receptor desensitization and endocytosis, 103
prompting the authors to conclude that arrestin3 is an overall negative
regulator of CXCR2 signaling in vivo. Similar results were reported in a cecal
ligation and puncture model of neutrophil infiltration, where arrestin3 null