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
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 (most notably G q/11). These
G-proteins dissociate into alpha (G-protein alpha-q/11) and
beta/gamma) subunits . Both subunits take part
in the activation of mitogen-activated protein kinase
G-protein alpha-q/11 and G-protein
beta/gamma act as signal transducers for activation of the Phospholipase C
beta (PLC-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 (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 .
Angiotensin II receptor, type-1 induces activation of
protein kinase II (CaMK II), PKC-delta
and PKC-epsilon. These kinases phosphorylate
PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) and
activate it , .
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)) , .
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 .
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 , ). 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 .
c-Src in turn may activates
Phospholipase C gamma 1 (PLC-gamma 1) that
plays the same role as PLC-beta .
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 , .
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.
Elk-1. Many of these factors can form different AP-1 complexes, e.g.
ATF-2/c-Jun  or
c-Jun/c-Fos . Thus, ERK and JNK signaling
cascades participate via activation of AP-1 in diverse of cellular functions .
- Goodfriend TL, Elliott ME, Catt KJ
Angiotensin receptors and their antagonists.
The New England journal of medicine 1996 Jun 20;334(25):1649-54
- Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE
Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor.
Nature 1991 May 16;351(6323):233-6
- Takayanagi R, Ohnaka K, Sakai Y, Nakao R, Yanase T, Haji M, Inagami T, Furuta H, Gou DF, Nakamuta M
Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor.
Biochemical and biophysical research communications 1992 Mar 16;183(2):910-6
- Luttrell LM, Daaka Y, Lefkowitz RJ
Regulation of tyrosine kinase cascades by G-protein-coupled receptors.
Current opinion in cell biology 1999 Apr;11(2):177-83
- Ushio-Fukai M, Griendling KK, Akers M, Lyons PR, Alexander RW
Temporal dispersion of activation of phospholipase C-beta1 and -gamma isoforms by angiotensin II in vascular smooth muscle cells. Role of alphaq/11, alpha12, and beta gamma G protein subunits.
The Journal of biological chemistry 1998 Jul 31;273(31):19772-7
- Thomas WG, Qian H, Smith NJ
When 6 is 9: 'uncoupled' AT1 receptors turn signalling on its head.
Cellular and molecular life sciences : CMLS 2004 Nov;61(21):2687-94
- Ginnan R, Singer HA
CaM kinase II-dependent activation of tyrosine kinases and ERK1/2 in vascular smooth muscle.
American journal of physiology. Cell physiology 2002 Apr;282(4):C754-61
- Du JQ, Sun CW, Tang JS
Effect of angiotensin II type 1 receptor on delayed rectifier potassium current in catecholaminergic CATH.a cells.
Acta pharmacologica Sinica 2004 Sep;25(9):1145-50
- Rocic P, Govindarajan G, Sabri A, Lucchesi PA
A role for PYK2 in regulation of ERK1/2 MAP kinases and PI 3-kinase by ANG II in vascular smooth muscle.
American journal of physiology. Cell physiology 2001 Jan;280(1):C90-9
- Riggins RB, DeBerry RM, Toosarvandani MD, Bouton AH
Src-dependent association of Cas and p85 phosphatidylinositol 3'-kinase in v-crk-transformed cells.
Molecular cancer research : MCR 2003 Apr;1(6):428-37
- Rocic P, Jo H, Lucchesi PA
A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle.
American journal of physiology. Cell physiology 2003 Dec;285(6):C1437-44
- Okabe S, Fukuda S, Kim YJ, Niki M, Pelus LM, Ohyashiki K, Pandolfi PP, Broxmeyer HE
Stromal cell-derived factor-1alpha/CXCL12-induced chemotaxis of T cells involves activation of the RasGAP-associated docking protein p62Dok-1.
Blood 2005 Jan 15;105(2):474-80
- Bubeck Wardenburg J, Pappu R, Bu JY, Mayer B, Chernoff J, Straus D, Chan AC
Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76.
Immunity 1998 Nov;9(5):607-16
- Murasawa S, Matsubara H, Mori Y, Masaki H, Tsutsumi Y, Shibasaki Y, Kitabayashi I, Tanaka Y, Fujiyama S, Koyama Y, Fujiyama A, Iba S, Iwasaka T
Angiotensin II initiates tyrosine kinase Pyk2-dependent signalings leading to activation of Rac1-mediated c-Jun NH2-terminal kinase.
The Journal of biological chemistry 2000 Sep 1;275(35):26856-63
- Touyz RM, Berry C
Recent advances in angiotensin II signaling.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 2002 Sep;35(9):1001-15
- Shah BH, Catt KJ
Calcium-independent activation of extracellularly regulated kinases 1 and 2 by angiotensin II in hepatic C9 cells: roles of protein kinase Cdelta, Src/proline-rich tyrosine kinase 2, and epidermal growth receptor trans-activation.
Molecular pharmacology 2002 Feb;61(2):343-51
- Hamaguchi A, Kim S, Yano M, Yamanaka S, Iwao H
Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension.
Journal of the American Society of Nephrology : JASN 1998 Mar;9(3):372-80
- Berk BC, Corson MA
Angiotensin II signal transduction in vascular smooth muscle: role of tyrosine kinases.
Circulation research 1997 May;80(5):607-16