Angiotensin's activation of Akt
via transactivation EGFR
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 pheochromocytomas .
It has been shown that angiotensin II may stimulate a
serine/threonine protein kinase (Akt) through
activate of p38 mitogen-activated protein kinase (p38 MAPK)
and transactivation of epidermal growth
factor receptor (EGFR) in vascular smooth muscle cells
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 . Both subunits take part
in this pathway activation Akt.
G alpha q/11 and G
beta/gamma act as signal transducers for activation of phospholipase C
beta (PLC-beta) .
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 alpha (PKC-alpha) and mobilise intracellular
Ca2+, respectively. These effectors are thought
to mediate most of the well-established acute responses to angiotensin
II, including vasoconstriction, aldosterone biosynthesis and thirst/salt
kinase II (CaMK II) and
(PKC-alpha), may activate of cytosolic
phospholipase A2, group-IVA
(PLA2G4A) , , , .
PLA2G4A hydrolyzes phosphatidylcholine
produce lyso-phosphatidylcholine and
arachidonic acid , , .
Further, arachidonic acid is metabolized by some enzymes
into hydroxyeicosatetraenoic and/or epoxyeicosatrienoic acids, which may activated p38
MAPK. For example, 12-lipoxygenase (ALOX12) converts
arachidonic acid to 12-hydroperoxyeicosatetraenoic acid
(12-HPETE) which than converts to 12-hydroxyeicosatetraenoic
acid (12-HETE) by glutathione peroxidase 1
(GPX1) and peroxiredoxin 6
It has been shown that 12-HETE activates small GTP
binding proteins: cell division cycle 42 (Cdc42) and
ras-related C3 botulinum toxin substrate 1 (Rac1) ,  and stimulates mitogen-activated protein kinase kinase kinase
11 (MLK3)/ dual specificity mitogen activated protein kinase
kinases (MEK3 and MEK6)/ p38
MAPK pathway , .
Isoforms p38 MAPKs (alpha, beta, gamma, delta) activate
phospholipase D2 (PLD2) and results in
1-acyl-2-arachidonoyl-glycerophosphate production, which
stimulates EGFR transactivation .
Transactivated EGFR in turn allows to activate
phosphatidylinositol 3-kinase (PI3K), which stimulates the
conversion of PI(4,5)P2 to phosphatidylinositol (3,4,5)
PI(3,4,5)P3 binds to the pleckstrin-homology domain of
Akt, recruits Akt to the plasma
membrane, and exposes Akt to phosphorylation at by
3-phosphoinositide-dependent protein kinase 1 (PDK) .
Phosphorylated and activated Akts stimulates several
downstream effectors, which regulate cell survival, cell cycle, glucose metabolism,
angiogenesis, vasomotor tone, and protein synthesis .
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