b-Arrestins in the Immune System - Progress in Molecular Biology and Translational Science - page 360

5.2.3 Lipid signaling receptors
Prostaglandins are lipid compounds derived from fatty acids. Prostaglandins
bind to their respective receptors to elicit functions including inflammatory
regulation. Prostaglandin E2 receptor (EP4) is a typical GPCR. Studies
suggested that b -arrestins have both positive and negative effects on the
EP4 receptor. b -Arrestin 1 is necessary for maximal agonist-induced inter-
nalization through the interaction with a Ser/Thr cluster in the C-terminal
domain of EP4 receptor. 94
Leukotrienes are arachidonic acid metabolites, binding to their respec-
tive receptors to elicit their role in inflammatory responses. b -Arrestin 1
is required for internalization of the leukotriene B4-activated leukotriene
B4 receptor. 95
Lysophosphatidylcholines are phospholipids that bind to G2A receptors
on PMNs recruiting clathrin, b -arrestin-1, and GRK6 for receptor desen-
sitization. Phospholipids cause acute lung injury 96 and are involved in

transfusion-related acute lung injury. 97

b -Arrestin 1 both propagates and

terminates inflammatory signals. 97
Lysophosphatidic acid binds to lysophosphatidic acid receptors, including
LPAR1, and mediates diverse biologic roles such as proliferation, platelet
aggregation, smooth muscle contraction, chemotaxis, fibroblast migration,
and tumor cell invasion. b -Arrestin1 andGRK2mediate lysophosphatidic acid
receptor LPAR1 desensitization. 98 Furthermore, b -arrestin2promotesa
distinct subset of ERK1/2-mediated responses to LPA receptor activation 99
and lysophosphatidic acid-induced NF- k B activation. 100 Suppression of
b -arrestin 2 expression using siRNA abolished chemotaxis induced by
lysophosphatidic acid. 86 b -Arrestin signaling regulates lysophosphatidic acid-

mediated migration and invasion of human breast tumor cells. 101
The phospholipid, platelet-activating factor (PAF), is an effective
chemoattractant that primes PMN oxidases. The binding of PAF with
the PAF receptor (PAFR or PTAFT) recruits b -arrestin 1 and desensitizes
the receptor. 102

b -Arrestin recruitment blocks both NF- k B activation and
Ca2 þ /calcineurin-dependent signaling pathways, leading to reduced cyto-
kine production. 103 Platelet-activating factor-induced clathrin-mediated
endocytosis requires a b -arrestin 1-MKK3-p38 MAPK complex and p38
MAPK activation. 104 Finally, the same scaffolding complex regulates actin
rearrangement in human neutrophils. 104,105

5.2.4 Protease-activated receptors
Both protease-activated receptor-1 (PAR-1) and PAR-2 mediate leukocyte
recruitment to sites of injury and infection. b -Arrestins may play a dual role