REGULATION OF ANGIOTENSIN-II-INDUCED JAK2 TYROSINE PHOSPHORYLATION - ROLES OF SHP-1 AND SHP-2

Angiotensin II (ANG II) exerts its effects on vascular smooth muscle c ells through G; protein-coupled AT(1) receptors. ANG II stimulation ac tivates the Janus kinase/signal transducers and activators of transcri ption (JAK/STAT) pathway by inducing tyrosine phosphorylation, activat ion, and association of JAK2 with the receptor. Association appears to be required for JAK2 phosphorylation. In the present study, electropo ration experiments with neutralizing anti-Src homology phosphatase-1 ( SHP-1) and anti-SHP-2 antibodies and time course determinations of SHP -1 and SHP-2 activation and complexation with JAK2 suggest that the ty rosine phosphatases, SHP-1 and SHP-2, have opposite roles in ANG II-in duced JAK2 phosphorylation. SHP-1 appears responsible for JAK2 dephosp horylation and termination of the ANG II-induced JAK/STAT cascade. SHP -2 appears to have an essential role in JAK2 phosphorylation and initi ation of the ANG II-induced JAK/STAT cascade leading to cell prolifera tion. The motif in the AT1 receptor that is required for association w ith JAK2 is also required for association with SHP-2. Furthermore, SHP -2 is required for JAK2-receptor association. SHP-2 may thus play a ro le as an adaptor protein for JAK2 association with the receptor, there by facilitating JAK2 phosphorylation and activation.