Angiotensin signaling via Beta-arrestin
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 type-1 mediates the major
cardiovascular effects of Angiotensin-II. It relate to
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, but
not in pheochromocytomas .
In general, mechanisms used by GPCRs to stimulate Mitogen-activated protein kinases
(MAPKs) fall into one of several broad categories. GPCR signal transduction via
Beta-arrestins is among recently recognized signaling
Upon binding with Angiotensin II,
Angiotensin II receptor type-1 is stabilized in its active
conformation and stimulates heterotrimeric G proteins dissotiation into alpha
(G-protein alpha q/11) and beta/gamma
(G-protein beta/gamma) subunits . Only G-protein beta/gamma takes part
in Beta-arrestin-dependent activation of MAPKs.
G-protein beta/gamma subunits, along with
Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2),
facilitate translocation of G-protein-coupled receptor kinases 2 and 3
(GRK2 and GRK3) to the plasma
membrane, where these GRKs phosphorylate the activated
Angiotensin II receptor type1. Phospholipid-bound
GRK5 and GRK6 undergo
autophosphorylation, which is required for receptor kinase activity. Then,
GRK5 and GRK6 phosphorylate the
activated Angiotensin II receptor type-1 independently of
G-protein beta/gamma .
GRK2, GRK5 and
GRK6 are inhibited by Ca('2+)/Calmodulin
, . The receptor-kinase activity of
GRK2 is enhanced if GRK2 is
phosphorylated by Protein kinase C conventional type (cPKC),
whereas receptor-kinase activity of GRK5 is diminished if
the GRK5 is phosphorylated by cPKC
Beta-arrestins are bound with agonist-stimulated and
GRKs-phosphorylated receptors only .
In addition, PKC phosphorylation sites have been mapped
to serine/threonine-rich regions in the COOH terminus of Angiotensin II
receptor type-1, which do not appear to be involved in
Beta-arrestin binding .
It has been clearly shown that internalization of the receptor and
Angiotensin II receptor type-1-mediated activation of
mitogen-activated protein kinase may be closely connected with
Beta-arrestin. In the case of GPCRs that bind tightly to
Beta-arrestin (such as the Angiotensin II
receptor type-1), multiprotein complex containing receptor,
Beta-arrestin, and activated MAPK internalize as a unit. It
results in accumulation of Mitogen-activated protein kinases 3, 1 and 10
(ERK1, ERK2 and
JNK3) and in endosomal vesicles , .
Agonist stimulation of Angiotensin II receptor type-1
promotes recruitment of a ternary complex containing V-src sarcoma viral oncogene homolog
(c-Src), Clathrin-associated protein complex (AP-2) and
Beta-arrestin. c-Src binds to
Beta-arrestin and an element of the AP-2 - beta 1 subunit of
Adapter-related protein complex 2 (Beta-adaptin 2). It would
stabilize the endocytic complex and allow the receptor to be efficiently targeted to the
Clathrin-coated pit (CCP) .
In addition, sustained Beta-arrestin ubiquitination is
required for its cotrafficking with activated receptor and for the generation of stable
compartmentalized ERK signals on endosomes. Activation of
Angiotensin II receptor type-1 by Angiotensin
II significantly increases binding of
Beta-arrestin2 and Mdm2 p53 binding protein homolog
(MDM2). It effectively shifts the equilibrium of
MDM2 subcellular distribution from nucleus to plasma
membrane. Functional consequences of the enhanced
promote ubiquitination of Beta-arrestin2 and assist
internalization of Angiotensin II receptor type-1 .
Beta-arrestin recruits components of MAP kinase modules
to the agonist-receptor complex at a step prior to, or coincident with, receptor
MAP kinase modules involve:
1) Proto-oncogen serine/threonine-protein kinase
(c-Raf-1), dual specificity Mitogen-activated protein kinase
kinase 1 (MEK1), ERK1
and ERK2 .
2) Apoptosis signal regulating kinase (ASK1),
Mitogen-activated protein kinase kinase 4 (MAP2K4),
There are two isoforms of Beta-arrestin, termed
Beta-arrestin2. Link between
Beta-arrestin isoforms and Angiotensin II
receptor type-1-mediated activation of the MAPK cascade remains unclear.
Physiological levels of Beta-arrestin1 may act as
"dominant-negative" inhibitors of Angiotensin II receptor
ERK activation . It has been shown that
Beta-arrestin1 participates in internalization of the GPCR
and binds to some elements of GPCR-mediated activation of MAPK , , .
- 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
- Shenoy SK, Lefkowitz RJ
Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling.
The Biochemical journal 2003 Nov 1;375(Pt 3):503-15
- 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
- Pitcher JA, Freedman NJ, Lefkowitz RJ
G protein-coupled receptor kinases.
Annual review of biochemistry 1998;67:653-92
- Wei H, Ahn S, Barnes WG, Lefkowitz RJ
Stable interaction between beta-arrestin 2 and angiotensin type 1A receptor is required for beta-arrestin 2-mediated activation of extracellular signal-regulated kinases 1 and 2.
The Journal of biological chemistry 2004 Nov 12;279(46):48255-61
- Kim J, Ahn S, Ren XR, Whalen EJ, Reiter E, Wei H, Lefkowitz RJ
Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling.
Proceedings of the National Academy of Sciences of the United States of America 2005 Feb 1;102(5):1442-7
- McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, Davis RJ, Lefkowitz RJ
Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3.
Science (New York, N.Y.) 2000 Nov 24;290(5496):1574-7
- Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, Lefkowitz RJ
Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds.
Proceedings of the National Academy of Sciences of the United States of America 2001 Feb 27;98(5):2449-54
- Fessart D, Simaan M, Laporte SA
c-Src regulates clathrin adapter protein 2 interaction with beta-arrestin and the angiotensin II type 1 receptor during clathrin- mediated internalization.
Molecular endocrinology (Baltimore, Md.) 2005 Feb;19(2):491-503
- Shenoy SK, Lefkowitz RJ
Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes.
The Journal of biological chemistry 2005 Apr 15;280(15):15315-24
- Ahn S, Wei H, Garrison TR, Lefkowitz RJ
Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2.
The Journal of biological chemistry 2004 Feb 27;279(9):7807-11
- DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW
beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
The Journal of cell biology 2000 Mar 20;148(6):1267-81
- Lin FT, Miller WE, Luttrell LM, Lefkowitz RJ
Feedback regulation of beta-arrestin1 function by extracellular signal-regulated kinases.
The Journal of biological chemistry 1999 Jun 4;274(23):15971-4
- Ge L, Shenoy SK, Lefkowitz RJ, DeFea K
Constitutive protease-activated receptor-2-mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and -2.
The Journal of biological chemistry 2004 Dec 31;279(53):55419-24