Activation of formyl peptide receptor-like 1 by WKYMVm induces serine phosphorylation of STAT3, which inhibits its tyrosine phosphorylation and nuclear translocation induced by hydrogen peroxide.
Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor that modulates the expression of several genes. The activation of STAT3 accompanies tyrosine phosphorylation and its translocation to the nucleus. Formyl peptide receptor like 1 (FPRL1) is an important classical chemoattractant receptor. In this study, we observed that the stimulation of FPRL1 by Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm) caused serine phosphorylation but not tyrosine phosphorylation of STAT3 in a pertussis toxin-sensitive manner. Moreover, downstream of FPRL1 stimulation, phospholipase D (PLD) activity was dramatically increased. n-butanol, a well-known phosphatidic acid (PA) acceptor, completely inhibited WKYMVm-induced STAT3 serine phosphorylation. Moreover, the exogenous addition of PA mimicked STAT3 phosphorylation by WKYMVm. We also found that WKYMVm stimulated extracellular signal regulated kinase (ERK), and that ERK activity is required for STAT3 serine phosphorylation. This WKYMVm-induced ERK activation was inhibited by n-butanol, whereas ERK activation was also induced by the addition of exogenous PA. In terms of the functional aspects of the WKYMVm-induced serine phosphorylation of STAT3, we found that hydrogen peroxide-stimulated STAT3 activation was blocked by pretreating WKYMVm. Taken together, we found that WKYMVm stimulated FPRL1, and that this resulted in STAT3 serine phosphorylation via PLD-mediated ERK activation, and that the serine phosphorylation of STAT3 blocked hydrogen peroxide-induced STAT3 activity.
Department of Biochemistry, College of Medicine, Dong-A University, Busan, 602-714, South Korea.
Eun Jin
EJ
Jo
Ha Young
HY
Lee
Jung Im
JI
Kim
Hyun-Kyu
HK
Kang
Youl-Nam
YN
Lee
Jong-Young
JY
Kwak
Yoe-Sik
YS
Bae
D001711:Biotransformation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D015151:Immunoblotting; D007202:Indicators and Reagents; D008156:Luciferases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D010739:Phospholipase D / Q000378:metabolism; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D050796:STAT3 Transcription Factor; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D013268:Stimulation, Chemical; D015534:Trans-Activators / Q000378:metabolism*; D014178:Translocation, Genetic / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; C469986:FPR1 protein, human; D007202:Indicators and Reagents; D009842:Oligopeptides; D016877:Oxidants; D044042:Receptors, Formyl Peptide; D043562:Receptors, G-Protein-Coupled; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; C113617:Trp-Lys-Tyr-Met-Val-Met; D014443:Tyrosine; D012694:Serine; D006861:Hydrogen Peroxide; D008156:Luciferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010739:Phospholipase D