Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells.
Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs. The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1 tyrosine dephosphorylation. In the present study, using specific enzyme inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c-Src, whereas tyrosine dephosphorylation is mediated by calcineurin. Calcineurin is activated in response to Ang II stimulation of VSMCs and is translocated to the nucleus. In addition, we show that Ang II-induced serine phosphorylation of STAT3 in VSMCs is mediated by mitogen-activated protein kinase and that dephosphorylation is mediated by protein phosphatase 2A (PP2A). PP2A translocates to the nucleus in response to Ang II stimulation of VSMCs and forms a complex with STAT3 in an Ang II-dependent manner.
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA.
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Marrero
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053614:Janus Kinase 2; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D054648:Protein Phosphatase 2; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; D019319:Okadaic Acid; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D016559:Tacrolimus