Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor

Abstract

The peptide angiotensin II is the effector molecule of the reninangiotensin system. All the haemodynamic effects of angiotensin II, including vasoconstriction and adrenal aldosterone release, are mediated through a single class of cell-surface receptors known as AT1 (refs 1, 2). These receptors contain the structural features of the G-protein-coupled receptor superfamily. We show here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that this phosphorylation is associated with increased activity of Jak2. The Jak family substrates STAT1 and STAT2 (for signal transducers and activators of transcription) are rapidly tyrosine-phosphorylated in response to angiotensin II. We also find that Jak2 co-precipitates with the AT1 receptor, indicating that G-protein-coupled receptors may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors.

Angiotensin II receptor pharmacology and AT1-receptor blockers

“…60,61 Recent reports link Ang II, through the AT 1 receptor, to the Jak/STAT signalling pathway. 62 This is a significant observation since the Jak/STAT pathway has been previously identified for cytokine receptors which leads to transcriptional activation of early growth-response genes, 63 and is now possibly also an important signalling pathway through which Ang II mediates its proliferative effects. 64 Interaction of Ang II with the Jak/STAT pathway has been observed in rat aortic smooth muscle cells.…”

“…64 Interaction of Ang II with the Jak/STAT pathway has been observed in rat aortic smooth muscle cells. 65 Ang II is able to rapidly phosphorylate tyrosine of the kinases Jak2 and Tyk2. Stimulation of Jak activity also leads to the phosphorylation of both STAT1 and STAT2 proteins, and subsequent translocation to the nucleus of the STAT1 protein.…”

Receptors and their classification: focus on angiotensin II and the AT2 receptor

“…59,60 This is a significant observation since the Jak/STAT pathway has been previously identified for cytokine receptors which leads to transcriptional activation of early growth-response genes, 61 and is now possibly also an important signalling pathway through which Ang II mediates its proliferative effects. 62 Generally, in response to ligand binding, Jak kinases associate with dimerized cytokine receptors, autophosphorylate, and activate signalling molecules via tyrosine phosphorylation, which in turn leads to association of the Jak substrates STAT1 and STAT2 and p48.…”

“…62 Interaction of Ang II with the Jak/STAT pathway has been observed in rat aortic smooth muscle cells. 60 Ang II is able to rapidly phosphorylate tyrosine of the kinases Jak2 and Tyk2. Stimulation of Jak activity also leads to the phosphorylation of both STAT1 and STAT2 proteins and subsequent translocation to the nucleus of the STAT1 protein.…”

Molecular and cellular mechanisms of action of angiotensin II (AT1) receptors in vascular smooth muscle

“…Stimulation of AT 1 receptors has recently been shown to induce activation of JAK2 and to a lesser extent TYK2 in rat aortic smooth muscle cells and in the same studies the AT 1 receptor was shown to co-immunoprecipitate with JAK2, but not with JAK1 or TYK2. 99 …”