ANGIOTENSIN-II-INDUCED TYROSINE PHOSPHORYLATION OF SIGNAL TRANSDUCERSAND 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) AT(1) receptors on vascular smooth muscle cell s (VSMCs) are coupled to the Janus-activated kinase (JAK)/signal trans ducers and activators of transcription (STAT) pathway. We have shown p reviously that Ang II stimulation of VSMCs results in the tyrosine pho sphorylation of JAK2 and STAT1 and the translocation of STAT1 to the n ucleus. In the present study, we demonstrate using specific enzyme inh ibitors and antisense oligonucleotides that both JAK2 and p59 Fyn tyro sine kinases are required for the Ang II-induced tyrosine phosphorylat ion and nuclear translocation of STAT1 in VSMCs, Neither tyrosine kina se, however, appears to function upstream from the other in a phosphor ylation cascade. Rather, p59 Fyn functions as an Ang II-activated dock ing protein for both JAK2 and STAT1, a docking interaction that may fa cilitate JAK2-mediated STAT1 tyrosine phosphorylation. In this study, we have also identified the nuclear dual-specificity phosphatase mitog en-activated protein kinase phosphatase 1 as the enzyme responsible fo r STAT1 tyrosine dephosphorylation in VSMCs.