Angiotensin II evokes a variety of biological responses by binding to a seven transmembrane cell surface receptor termed AT1. Ligand binding to the AT1receptor induces the physical association and activation of the intracellular kinase Jak2. To elucidate the mechanism of this association, COS-7 cells were co-transfected with the AT1receptor and either wild type Jak2 or a catalytically inactive Jak2. AT1receptor–Jak2 association was assessedin vitroby a GST-AT1receptor fusion protein binding assay andin vivoby direct co-immunoprecipitation of the receptor–Jak2 complex. Both studies showed that Jak2 must be catalytically active to form a complex with the AT1receptor, and that complex formation is associated with Jak2 tyrosine phosphorylation. These results were confirmed using the Jak2 specific inhibitor AG-490. We also found that over-expression of wild type Jak2 in COS-7 cells leads toin vivocomplex formation of spontaneously autophosphorylated Jak2 with the AT1receptor. No such complex formation was observed with a dominant negative Jak2. Thus, the physical association of Jak2 with the AT1receptor is regulated by an angiotensin II mediated autophosphorylation event.