Biology Reference
In-Depth Information
5.4. Other non-GPCR signaling pathways
Peroxisome proliferator-activated receptors are nuclear receptor proteins,
regulating metabolism and inflammation.
b
-Arrestin 1 binds peroxisome
proliferator-activated receptor-
g
(PPAR
g
) to elicit the repression of
PPAR
g
/9-
cis
-retinoic acid receptor-
a
function and to promote PPAR
g
/
nuclear receptor corepressor function in PPAR
g
-mediated adipogenesis
and inflammatory cytokine expression.
123
TNF
a
binds to its receptor, a type I transmembrane protein, recruiting
death domain-containing proteins and leading to activation of apoptotic
pathways. As TNF
a
is such a pleiotropic cytokine, the interaction of
TNF and its cognate receptor regulates an array of biological functions
including apoptosis, immune regulation, and inflammatory responses.
b
-Arrestin 1 can function as a signaling molecule in the TNF
a
action cascade
that stimulates ERK activation and lipolysis, mediates phosphatidylinositol
3-kinase activation and inflammatory gene expression.
60
b
-Arrestins 1
and 2 also bind and prevent degradation of I
k
B
a
, inhibiting NF-
k
B
activation
124,125
and leading to the suppression of TNF
a
-induced
proinflammatory cytokines. A subsequent report confirmed that although
TNF receptor-1 is a non-GPCR, it functions through a G
a
q/11 signaling
complex and ERK activation, mediating TNF
a
-induced pho-
sphatidylinositol 3-kinase activation and inflammatory gene expression.
126
b
-Arrestin 1 was found to interact with STAT1 upon interferon-
g
stimula-
tion.
127
b
-Arrestin 1 accelerates STAT1 tyrosine dephosphorylation by rec-
ruiting T-cell protein tyrosine phosphatase (TC45) and negatively regulates
interferon-
g
-induced gene transcription.
127
Interestingly,
b
-arrestin 2 did
not have a similar effect in regulating interferon-
g
signaling, although
b
-arrestin 2 also binds to STAT1.
TGF-
b
binds to TGF-
b
receptors, regulating cell growth, differentia-
tion, and immune responses.
b
-Arrestin 2, but not
b
-arrestin 1, binds to
the phosphorylated type III TGF-
b
receptor and mediates endocytosis of
the type II TGF-
b
receptor/type III TGF-
b
receptor complex.
128
Further
study suggested that
b
-arrestin 2 modulates the association of type III TGF-
b
receptor with ALK6 and ALK3 and enhances ALK6-mediated bone mor-
phogenetic protein 2 signaling.
129
TGF-
b
signaling mediates immune reg-
ulation, inflammatory responses, and tissue fibrosis. However, functional
studies on
b
-arrestin-mediating TGF-
b
signaling are largely lacking. Inter-
action of
b
-arrestin 2 and type III TGF-
b
receptors regulates epithelial cell
migration through activation of Cdc42.
130
In a tissue fibrosis model, our
Search WWH ::
Custom Search