THESIS
2011
xiv, 158 p. : ill. (some col.) ; 30 cm
Abstract
Inflammatory response is important for our protection against infections and injuries, whereas uncontrolled inflammatory response could become destructive. Recent studies suggested that G protein signaling is involved in regulating different components of the inflammatory pathway. G protein-coupled receptors, for example formyl-peptide receptor like 1 (FPRL-1), somatostatin type 2 receptor (SSTR2) and α
2-adrenergic receptor have been shown to couple with Gα
i and Gα
q family proteins (in particular Gα
14) and lead to activation of downstream effectors such as NFκB and STAT3. Gα
14 is expressed in many immune cells. However, their function in inflammation and immune responses as well as the signaling mechanism of such function remain to be identified. In my current study, I found that activa...[
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Inflammatory response is important for our protection against infections and injuries, whereas uncontrolled inflammatory response could become destructive. Recent studies suggested that G protein signaling is involved in regulating different components of the inflammatory pathway. G protein-coupled receptors, for example formyl-peptide receptor like 1 (FPRL-1), somatostatin type 2 receptor (SSTR2) and α
2-adrenergic receptor have been shown to couple with Gα
i and Gα
q family proteins (in particular Gα
14) and lead to activation of downstream effectors such as NFκB and STAT3. Gα
14 is expressed in many immune cells. However, their function in inflammation and immune responses as well as the signaling mechanism of such function remain to be identified. In my current study, I found that activation of FPRL-1 by WKYMVM in U87 astrocytoma cells leads to Ca
2+ mobilization via Gα
i proteins and store-operated channels. On the other hand, activation of FPRL-1 in THP-1 monocytic cells leads to STAT3 and IKK phosphorylation via Gα
14/Gα
16. I also found that Gα
14 mediates NFκB and STAT3 activation via interaction with TPR1 and subsequent activation of the Ras/ERK signaling pathway. Disruption of the Gα
14/TPR1 interaction by either overexpression of the dominant negative mutant of TPR1 (TPR1ΔC) or siRNA targeting TPR1 significantly reduced Gα
14-induced Ras activation, as well as ERK, IKK and STAT3 Serine
727 phosphorylation. Moreover, using a series of Gα
14/Gα
z chimeras, I have shown that Gα
14 may utilize structural regions different from Gα
16 and Gα
q for PLCβ and TPR1-interaction. My results suggested that the N-terminal of Gα
14 is important for the interaction with TPR1 and the activation of PLCβ. Collectively, results from the present study show that G
i-coupled receptors can employ Gα
14 in endogenous cellular systems for NFκB and STAT3 activation through G
14/TPR1 interaction and activation of the Ras/ERK signaling pathway. By means of G
14-regulated pathways, many GPCRs may possess the ability to modulate pro-inflammatory responses as well as other immune responses under physiological conditions.
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