| 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 α2-adrenergic receptor have been shown to couple with Gαi and Gαq family proteins (in particular Gα14) and lead to activation of downstream effectors such as NFκB and STAT3. Gα14 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 Ca2+ mobilization via Gαi 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 Gα14 /Gα16. I also found that Gα14 mediates NFκB and STAT3 activation via interaction with TPR1 and subsequent activation of the Ras/ERK signaling pathway. Disruption of the Gα14/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 Gα14/Gα z chimeras, I have shown that Gα14 may utilize structural regions different from Gα16 and Gαq for PLCβ and TPR1-interaction. My results suggested that the N-terminal of Gα14 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 Gα14 in endogenous cellular systems for NFκB and STAT3 activation through G14/TPR1 interaction and activation of the Ras/ERK signaling pathway. By means of G14-regulated pathways, many GPCRs may possess the ability to modulate pro-inflammatory responses as well as other immune responses under physiological conditions. |
