Development - Angiotensin signaling via STATs

Angiotensin signaling via STAT

Angiotensin II, a major effector peptide of the renin-angiotensin system, is now believed to play a critical role in the pathogenesis of cardiovascular remodeling associated with hypertension, heart failure, and atherosclerosis. [1]

Angiotensin II receptor type1 mediates the major cardiovascular effects of angiotensin II. It relate to guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR) superfamily. [2] The human angiotensin II receptor type1 is found in liver, lung, adrenal, and adrenocortical adenomas, but not in pheochromocytomas. [3]

Janus kinase/signal transducer and activator of transcription (STAT) pathway play a very important role in transduction of angiotensin II- induced signals. It pathway was initially discovered as a major cytokine signal transduction pathway.

Angiotensin II, after its interaction with the angiotensin II receptor type1, causes directly activation of tyrosine-protein kinase 2 (Jak2) and non-receptor tyrosine-protein kinase (Tyk2), which then activates different STATs (STAT1, STAT2, STAT3, STAT5) under different experimental conditions. [4], [5], [6] Thus, angiotensin II receptor type1 may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors. [4]

It is shown that STAT1 may be regulated by proto-oncogene tyrosine-protein kinase (Fyn) and dual specificity protein phosphatase 1 (MKP-1).

Fyn serves as an angiotensin II-activated docking protein bringing Jak2 and STAT1 together, thereby facilitating Jak2-mediated STAT1 phosphorylation [7] MKP-1 is the phosphatase responsible for STAT1 dephosphorylation and inactivation in VSMCs. [8]

In contrast to the case of angiotensin II-induced tyrosine phosphorylation of STAT1, angiotensin II-induced tyrosine phosphorylation of STAT3 in VSMCs requires proto-oncogene tyrosine-protein kinase (c-Src). In that case, STAT3 is dephosphorylated by PP2A and calcineurin. Serine/threonine protein phosphatase 2A (PP2A) and serine/threonine protein phosphatase calcineurin translocates to the nucleus in response to angiotensin II stimulation of VSMCs and transiently forms a complex with STAT3 just prior to the time during which STAT3 becomes serine-dephosphorylated. [9]

In addition, angiotensin II may activates Janus kinase/STAT pathway via G protein-dependent pathway. [10]

Upon binding with angiotensin II, the angiotensin II receptor type1 is stabilized in its active conformation and stimulates heterotrimeric G proteins (most notably G q/11). These Gq/11-proteins dissociate into alpha (G alpha q/11) and beta/gamma (G beta/gamma) subunits. [11]

G beta/gamma acts as a signal transducer for activation of phospholipase C beta (PLC-beta) by G alpha q/11 [12] PLC-beta activation leads to hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and the generation of diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG and IP3 stimulate protein kinase C, type delta (PKC-delta) and mobilise intracellular Ca²⁺, respectively. [13]

Angiotensin II receptor type1-mediated signals, Ca²⁺ (via intermediate, presumably - Ca²⁺/calmodulin-dependent protein kinase II (CaMK II)) [14], [15]) and PKC-delta, activate proline-rich tyrosine kinase 2 (Pyk2). Pyk2 in turn activate preassociated Jak2, (e.g., through recruitment and activation of c-Src). [10]

Activated STATs translocate into the nucleus and regulates gene expression (e.g., c-fos) through binding to specific sequences. In addition, STAT1, STAT2 and interferon-stimulated transcription factor 3, gamma 48kDa (IRF9) may form interferon-stimulated gene factor 3 complex (ISGF3 complex), which initiates the transcription of early growth response genes. [16]

The angiotensin II-induced Janus kinase/STAT pathway plays an essential role in cellular proliferation, the inflammatory response, development of cardiovascular diseases and other. [10]

References:

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