Angiotensin activation of MAPKs via Pyk2
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
atherosclerosis. [1]
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. [2] Human Angiotensin II receptor,
type-1 is found in liver, lung, adrenal, and adrenocortical adenomas
[3].
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 (most notably G q/11). These
G-proteins dissociate into alpha (G-protein alpha-q/11) and
beta/gamma (G-protein
beta/gamma) subunits [4]. Both subunits take part
in the activation of mitogen-activated protein kinase
cascade.
G-protein alpha-q/11 and G-protein
beta/gamma act as signal transducers for activation of the Phospholipase C
beta (PLC-beta) [5].
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 (e.g.,
PKC-delta and PKC-epsilon) and
mobilize intracellular Ca2+, respectively.
These effectors are believed to mediate most of the well established acute
responses to Angiotensin II, including vasoconstriction,
aldosterone biosynthesis and thirst/salt appetite [6].
Angiotensin II receptor, type-1 induces activation of
Ca2+/Calmodulin-dependent
protein kinase II (CaMK II), PKC-delta
and PKC-epsilon. These kinases phosphorylate
PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) and
activate it [7], [8].
Pyk2(FAK2) is a key tyrosine kinase in the early events
of the Angiotensin II signaling. It is a point of split of
the Angiotensin II signaling.
Pyk2(FAK2)-dependent phosphorylation and interaction with
the adapter molecule protein Crk-associated substrate
(p130CAS) lead to their association with the p85 regulatory
subunit of Phosphatidylinositol 3-kinase (PI3K reg class 1A
(p85)) [9], [10].
This complex formation leads to the activation of PI3K and to regulation of important
cell processes, e.g., protein synthesis via regulation of the Eukaryotic initiation
factor 4E (eIF4E)/eIF4E-bindind protein (4E-BP) complex [11].
Pyk2(FAK2) is the main mediator responsible for the
transmission of Angiotensin II signals to Ras-related C3
botulinum toxin substrate 1 (Rac1) via, e.g, Guanine
nucleotide exchange factor VAV-1 [12], [13]). Activated Rac1 stimulates the cascade that
involves p21-Activated kinase 1 (PAK1)/ Mitogen-activated
protein kinase kinase kinase 1 (MEKK1)/ Dual specificity
mitogen-activated protein kinase kinase 4 (MEK4)/c-Jun
N-terminal kinase (JNK(MAPK8-10)). Tyrosine-protein kinase
v-Src sarcoma viral oncogene homolog (c-Src) is also
partially involved in Rac1 activation [14].
c-Src in turn may activates
Phospholipase C gamma 1 (PLC-gamma 1) that
plays the same role as PLC-beta [15].
In additional, Pyk2(FAK2) acts as an upstream regulator
of two parallel signaling pathways, ERK and PI3K pathways. The formation of the complex
between Src homology 2 domain containing transforming protein
(Shc) and Growth factor receptor bound 2
(GRB2) leads to activation of
the Son of sevenless proteins (SOS)/ v-Ha-ras Harvey rat
sarcoma viral oncogene homolog (H-Ras)/ 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)
cascade [9], [16].
Activation by Angiotensin II leads to nuclear
translocation of the ERK1, ERK2
and JNK(MAPK8-10) kinases, as well as to
activation of transcription factors, e.g.
c-Fos, c-Jun,
ATF-2, and
Elk-1. Many of these factors can form different AP-1 complexes, e.g.
ATF-2/c-Jun [14] or
c-Jun/c-Fos [17]. Thus, ERK and JNK signaling
cascades participate via activation of AP-1 in diverse of cellular functions [18].
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