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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
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