Angiotensin II effects on STAT3 phosphorylation in cardiomyocytes: evidence for Erk-dependent Tyr705 dephosphorylation.
Experiments were performed to define the basis for negative regulation of STAT3 activation (i.e., Tyr705 phosphorylation) by angiotensin II in cardiomyocytes. Treatment of cardiomyocytes with angiotensin II resulted in rapid and sustained phosphorylation of STAT3 on Ser727; in contrast, STAT3 Tyr705 phosphorylation was decreased, with dephosphorylation being most pronounced at 30 minutes. Angiotensin II-induced STAT3 Tyr705 dephosphorylation was not prevented by inhibiting protein synthesis, but was blocked by vanadate or the MEK inhibitor PD98059. PD98059 was found to inhibit angiotensin II-induced Erk activation and STAT3 Ser727 phosphorylation. Angiotensin II also attenuated LIF-induced STAT3 Tyr705 phosphorylation, and this effect could be blocked with PD89059. These results are consistent with Erk-mediated STAT3 Ser727 phosphorylation leading to STAT3 Tyr705 dephosphorylation, and accounting for angiotensin II-mediated STAT3 inhibition in cardiomyocytes. We propose that Erk serves as a scaffolding protein in recruiting either a protein tyrosine or MAP kinase phosphatase to STAT3.
Booz
George W
GW
Texas A&M University System, Health Science Center, College of Medicine, Cardiovascular Research Institute, Division of Molecular Cardiology, 1901 South 1st Street, Bldg 162 Temple 76504, USA. gbooz@medicine.tamu.edu
Day
Jonathan N E
JN
Baker
Kenneth M
KM
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D053605:Leukemia Inhibitory Factor; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014638:Vanadates / Q000494:pharmacology
D004268:DNA-Binding Proteins; D005419:Flavonoids; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D000804:Angiotensin II; D019000:Phosphotyrosine; D014638:Vanadates; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one