Angiotensin's activation of ERK
via transactivation of EGFR
Angiotensin II, a major effector peptide of the
renin-angiotensin system, is believed to play a critical role in the pathogenesis of
cardiovascular remodeling associated with hypertension, heart failure, and
Angiotensin II receptor, type-1 mediates major
cardiovascular effects of Angiotensin II. It belongs to the
guanine nucleotide-binding regulatory protein (G protein)-coupled receptor (GPCR)
superfamily.  Human Angiotensin II receptor,
type-1 is found in liver, lung, adrenal, and adrenocortical adenomas
In general terms, the mechanisms used by GPCRs to stimulate mitogen-activated protein
kinases (MAPKs) fall into one of several broad categories. One of the important
mechanisms involves the cross-talk between GPCRs and classical receptor tyrosine kinase,
e.g., Epidermal growth factor receptor (EGFR). This process
is called transactivation.
Upon binding with Angiotensin II the
Angiotensin II receptor, type-1 is stabilized in its active
conformation and stimulates heterotrimeric G proteins. In many Angiotensin
II target cells, the Angiotensin II receptor, type-1
interacts primarily with Gq/11 proteins.
However, the angiotensin II receptor, type-1 is also coupled
with Gi proteins in hepatocytes ,  and in adrenal,
pituitary, and renal cells , . These G-proteins
dissociate into alpha (G-protein alpha-q/11
and G-protein alpha-i family) and
beta/gamma) subunits . Both subunits take part
in the activation of mitogen-activated protein kinase
G-protein alpha-q/11 and/or G-protein
beta/gamma activate the v-Src sarcoma viral oncogene homolog
(c-Src) . In addition, G alpha and G
beta/gamma subunits act as signal transducers for activation of the Phospholipase C beta
PLC-beta activation leads to hydrolysis of
Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and
formation of Diacylglycerol (DAG) and Inositol trisphosphate
(IP3). DAG and
IP3 stimulate the Protein kinase C, type delta
(PKC-delta) and mobilize intracellular
Ca2+, respectively .
Angiotensin II receptor, type-1 induces activation of
protein kinase II (CaMK II) and
PKC-delta. Both kinases phosphorylate PTK2B protein tyrosine
kinase 2 beta (Pyk2(FAK2)) and activate
Pyk2(FAK2)/ c-Src kinase
complex , , , .
Activated c-Src is a key intermediate in transactivation
of the EGFR through metalloproteases (ADAMs, e.g.
ADAM12)/ Heparin-binding EGF-like growth factor
Like other members of the EGF family, HB-EGF is
synthesized as a membrane-anchored insoluble form and then processed to a bioactive
soluble form. This process is called ectodomain shedding .
HB-EGF activates EGFR and
stimulates EGFR phosphorylation by
After EGFR phosphorylation, this receptor recruits
adaptor proteins (Src homology 2 domain containing transforming protein
(Shc) and Growth factor receptor bound 2
(GRB2)) Then, these adaptor proteins are activated by
Pyk2(FAK2) and c-Src , .
Activated Shc and GRB2
recruit Son of sevenless proteins (SOS) for
the small GTPase H-Ras. This results in rapid activation of
the H-Ras and subsequentl activation of the v-Raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1)/
Mitogen-activated protein kinase kinase 1 and 2
(MEK1 and MEK2)/ Mitogen-activated protein kinases 1 and 3 (ERK2 and ERK1)
kinase cascade .
Activation by Angiotensin II leads to nuclear
translocation of the ERK1 and ERK2 and further
to activation of certain transcription factors (e.g.,
c-Fos, Elk-1). Thus, ERK
signaling cascade participates in a diversity of cellular functions .
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