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Requirement of Ca²⁺ and PKC for Janus Kinase 2 Activation by Angiotensin II: Involvement of PYK2

Department of Biochemistry (G.D.F., S.S., T.I., S.E.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; Department of Anatomy and Physiology (E.D.M.), Meharry Medical College, Nashville, Tennessee 37208; Department of Biochemistry (T.S.), Sapporo Medical University, Sapporo 060-8556, Japan; and Institute of Molecular Oncology (M.O., T.K.), Showa University, Tokyo 142-8555, Japan

Address all correspondence and requests for reprints to: Satoru Eguchi, M.D., Ph.D., Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. E-mail: satoru.eguchi{at}vanderbilt.edu

In vascular smooth muscle cells, angiotensin II (AngII) stimulates association of its G protein-coupled AngII type 1 (AT₁) receptor with Janus kinase 2 (JAK2), resulting in the activation of signal transducer and activator of transcription proteins. Although the association and activation of subsequent signal transducer and activator of transcription proteins appear to prerequire JAK2 activation, the signaling mechanism by which the AT₁ receptor activates JAK2 remains uncertain. Here, we have examined the signaling mechanism required for JAK2 activation by AngII in vascular smooth muscle cells. We found that AngII, through the AT₁ receptor, rapidly stimulated JAK2 phosphorylation at Tyr^1007/1008, the critical sites for the kinase activation. By using selective agonists and inhibitors, we demonstrated that PLC and its derived signaling molecules, phosphatidylinositol triphosphate/Ca²⁺ and diacylglycerol/PKC, were essential for AngII-induced JAK2 phosphorylation. The PKC isoform required for JAK2 activation appears to be PKC since a selective PKC but not PKC/ß inhibitor and dominant-negative PKC overexpression inhibited JAK2 activation. We further examined a link between JAK2 and a Ca²⁺/PKC-sensitive tyrosine kinase, PYK2. We found that PYK2 activation by AngII requires PKC, and that PYK2 associates with JAK2 constitutively. Moreover, transfection of two distinct PYK2 dominant-negative mutants markedly inhibited AngII-induced JAK2 activation. From these data we conclude that AT₁-derived signaling molecules, specifically Ca²⁺ and PKC, participate in AngII-induced JAK2 activation through PYK2. These data provide a new mechanistic insight by which the hormone AngII exerts its cytokine-like actions in mediating vascular remodeling.

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