Lysophosphatidic acid inhibits epidermal-growth-factor-induced Stat1 signaling in human epidermoid carcinoma A431 cells.
Lysophosphatidic acid (LPA) is a lipid mediator which acts on its putative G protein-coupled receptor (GPCR). Recently, activation of signal transducers and activators of transcription (STATs) mediated by GPCR has been reported. In this study, we examined the effect of LPA on STAT activation using the electrophoretic mobility shift assays and the heterologous promoter analysis in human epidermoid carcinoma A431 cells. We found that LPA inhibited epidermal growth factor (EGF)-induced Stat1 activation in a concentration-dependent manner. Other phospholipase C (PLC)-coupled GPCR agonists, bradykinin and ATP, also inhibited Stat1 activation. This inhibitory effect of LPA was completely mimicked by an activator of protein kinase C (PKC), a PLC-downstream effector. These findings suggest that the inhibitory effect on EGF-induced Stat1 activation may be a general characteristic of PLC-coupled GPCRs and PKC pathway may be mainly associated with this inhibitory effect. This is the first evidence showing that GPCR agonists inhibit the Janus kinase-independent Stat1 activation induced by receptor tyrosine kinase.
Suzuki
Y
Y
Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan.
Ozawa
Y
Y
Murakami
K
K
Miyazaki
H
H
D001920:Bradykinin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D004837:Epinephrine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D004268:DNA-Binding Proteins; D008246:Lysophospholipids; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D004815:Epidermal Growth Factor; D011493:Protein Kinase C; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D013755:Tetradecanoylphorbol Acetate; D001920:Bradykinin; D004837:Epinephrine