The angotensin II-dependent nuclear translocation of Stat1 is mediated by the Jak2 protein motif (YRFRR)-Y-231

In response to angiotensin II, Jak2 autophosphorylates and binds the angiot ensin II AT(1) receptor. By studying a variety of Jak2 deletion proteins, w e now show that the Jak2 protein motif (YRFRR)-Y-231 is required for the co -association of this kinase with the AT(1) receptor. We also used a full-le ngth Jak2 protein containing a (231)FAAAA amino acid substitution. Although this protein still autophosphorylated in response to angiotensin II, it di d not co-associate with the AT(1) receptor. This uncoupling indicates that AT(1)/Jak2 co-association is not necessary for angiotensin II-induced Jak2 autophosphorylation and that Jak2 autophosphorylation per se is insufficien t for AT, receptor co-association, In response to angiotensin II, the Jak2- (231)FAAAA mutant will tyrosine phosphorylate Stat1. However, in the absenc e of AT(1)/Jak2 co-association, Stat1 did not translocate into the cell nuc leus and failed to mediate gene transcription. This notable result indicate s that Stat1 tyrosine phosphorylation alone is insufficient for Stat1 nucle ar translocation. In summary, we now show that, although Jak2-mediated tyro sine phosphorylation of Stat1 is independent of receptor co-association, Ja k2-mediated recruitment of Stat1 to the AT, receptor is critical for Stat1 nuclear translocation and subsequent gene transcription.