Angiotensin II-induced tyrosine phosphorylation of signal transducers and activators of transcription 1 is regulated by Janus-activated kinase 2 and Fyn kinases and mitogen-activated protein kinase phosphatase 1.
Angiotensin II (Ang II) AT1 receptors on vascular smooth muscle cells (VSMCs) are coupled to the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that Ang II stimulation of VSMCs results in the tyrosine phosphorylation of JAK2 and STAT1 and the translocation of STAT1 to the nucleus. In the present study, we demonstrate using specific enzyme inhibitors and antisense oligonucleotides that both JAK2 and p59 Fyn tyrosine kinases are required for the Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT1 in VSMCs. Neither tyrosine kinase, however, appears to function upstream from the other in a phosphorylation cascade. Rather, p59 Fyn functions as an Ang II-activated docking protein for both JAK2 and STAT1, a docking interaction that may facilitate JAK2-mediated STAT1 tyrosine phosphorylation. In this study, we have also identified the nuclear dual-specificity phosphatase mitogen-activated protein kinase phosphatase 1 as the enzyme responsible for STAT1 tyrosine dephosphorylation in VSMCs.
Venema
R C
RC
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912, USA.
Venema
V J
VJ
Eaton
D C
DC
Marrero
M B
MB
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators; D000804:Angiotensin II; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C494961:Fyn protein, rat; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D051076:Proto-Oncogene Proteins c-fyn; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases