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
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.  The human
angiotensin II receptor type1
is found in liver, lung, adrenal, and adrenocortical adenomas, but not in
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. , ,  Thus,
angiotensin II receptor type1 may be able to signal through the
intracellular phosphorylation pathways used by cytokine receptors. 
It is shown that STAT1 may be regulated by
proto-oncogene tyrosine-protein kinase
dual specificity protein phosphatase 1
Fyn serves as an angiotensin
II-activated docking protein bringing Jak2
and STAT1 together, thereby facilitating
phosphorylation  MKP-1 is the phosphatase
responsible for STAT1 dephosphorylation and inactivation in
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. 
In addition, angiotensin II may activates
Janus kinase/STAT pathway via G
protein-dependent pathway. 
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. 
G beta/gamma acts as a signal transducer for activation
of phospholipase C beta (PLC-beta) by G alpha
q/11  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. 
Angiotensin II receptor type1-mediated signals,
Ca2+ (via intermediate, presumably -
Ca2+/calmodulin-dependent protein kinase II (CaMK
II)) , ) 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). 
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. 
The angiotensin II-induced Janus kinase/STAT pathway
plays an essential role in cellular proliferation, the inflammatory response, development
of cardiovascular diseases and other. 
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