Platelet-activating Factor-induced Chemokine Gene Expression Requires NF-κB Activation and Ca2+/Calcineurin Signaling Pathways
Previously, we reported that platelet-activating factor (PAF) stimulates higher G protein activation and a more robust Ca 2+ mobilization in RBL-2H3 cells expressing carboxyl terminus deletion, phosphorylation-deficient mutant of PAF receptor (mPAFR) when compared with the wild-type receptor (PAFR)....
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Published in | The Journal of biological chemistry Vol. 279; no. 43; p. 44606 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
22.10.2004
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Abstract | Previously, we reported that platelet-activating factor (PAF) stimulates higher G protein activation and a more robust Ca 2+ mobilization in RBL-2H3 cells expressing carboxyl terminus deletion, phosphorylation-deficient mutant of PAF receptor (mPAFR)
when compared with the wild-type receptor (PAFR). However, PAF did not provide sufficient signal for CC chemokine receptor
ligand 2 (CCL2) production in cells expressing mPAFR. Based on these findings, we hypothesized that receptor phosphorylation
provides a G protein-independent signal that synergizes with Ca 2+ mobilization to induce CCL2 production. Here, we show that a mutant of PAFR (D289A), which does not couple to G proteins,
was resistant to agonist-induced receptor phosphorylation. Unexpectedly, we found that when this mutant was coexpressed with
mPAFR, it restored NF-κB activation and CCL2 production. PAF caused translocation of β-arrestin from the cytoplasm to the
membrane in cells expressing PAFR but not a phosphorylation-deficient mutant in which all Ser/Thr residues were replaced with
Ala (ÎST-PAFR). Interestingly, PAF induced significantly higher NF-κB and nuclear factor of activated T cells (NFAT)-luciferase
activity as well as CCL2 production in cells expressing ÎST-PAFR than those expressing PAFR. Furthermore, a Ca 2+ /calcineurin inhibitor completely inhibited PAF-induced NFAT activation and CCL2 production but not NF-κB activation. These
findings suggest that the carboxyl terminus of PAFR provides a G protein-independent signal for NF-κB activation, which synergizes
with G protein-mediated Ca 2+ /calcineurin activation to induce CCL2 production. However, receptor phosphorylation and β-arrestin recruitment inhibit CCL2
production by blocking both NF-κB activation and Ca 2+ /calcineurin-dependent signaling pathways. |
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AbstractList | Previously, we reported that platelet-activating factor (PAF) stimulates higher G protein activation and a more robust Ca 2+ mobilization in RBL-2H3 cells expressing carboxyl terminus deletion, phosphorylation-deficient mutant of PAF receptor (mPAFR)
when compared with the wild-type receptor (PAFR). However, PAF did not provide sufficient signal for CC chemokine receptor
ligand 2 (CCL2) production in cells expressing mPAFR. Based on these findings, we hypothesized that receptor phosphorylation
provides a G protein-independent signal that synergizes with Ca 2+ mobilization to induce CCL2 production. Here, we show that a mutant of PAFR (D289A), which does not couple to G proteins,
was resistant to agonist-induced receptor phosphorylation. Unexpectedly, we found that when this mutant was coexpressed with
mPAFR, it restored NF-κB activation and CCL2 production. PAF caused translocation of β-arrestin from the cytoplasm to the
membrane in cells expressing PAFR but not a phosphorylation-deficient mutant in which all Ser/Thr residues were replaced with
Ala (ÎST-PAFR). Interestingly, PAF induced significantly higher NF-κB and nuclear factor of activated T cells (NFAT)-luciferase
activity as well as CCL2 production in cells expressing ÎST-PAFR than those expressing PAFR. Furthermore, a Ca 2+ /calcineurin inhibitor completely inhibited PAF-induced NFAT activation and CCL2 production but not NF-κB activation. These
findings suggest that the carboxyl terminus of PAFR provides a G protein-independent signal for NF-κB activation, which synergizes
with G protein-mediated Ca 2+ /calcineurin activation to induce CCL2 production. However, receptor phosphorylation and β-arrestin recruitment inhibit CCL2
production by blocking both NF-κB activation and Ca 2+ /calcineurin-dependent signaling pathways. |
Author | Christopher Nuesch Asifa K. Zaidi Hydar Ali Jasimuddin Ahamed Rampura T. Venkatesha |
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Snippet | Previously, we reported that platelet-activating factor (PAF) stimulates higher G protein activation and a more robust Ca 2+ mobilization in RBL-2H3 cells... |
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Title | Platelet-activating Factor-induced Chemokine Gene Expression Requires NF-κB Activation and Ca2+/Calcineurin Signaling Pathways |
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