Development - Angiotensin signaling via beta-Arrestin

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 atherosclerosis [1].

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. [2] Human Angiotensin II receptor type-1 is found in liver, lung, adrenal, and adrenocortical adenomas, but not in pheochromocytomas [3].

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 mechanisms [4].

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 [5]. 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 [6].

GRK2, GRK5 and GRK6 are inhibited by Ca('2+)/Calmodulin [6], [7]. 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 [6].

Beta-arrestins are bound with agonist-stimulated and GRKs-phosphorylated receptors only [8].

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 [7].

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 [9], [10].

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) [11].

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 Beta-arrestin2/MDM2 interaction promote ubiquitination of Beta-arrestin2 and assist internalization of Angiotensin II receptor type-1 [12].

Beta-arrestin recruits components of MAP kinase modules to the agonist-receptor complex at a step prior to, or coincident with, receptor internalization.

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 [10].

2) Apoptosis signal regulating kinase (ASK1), Mitogen-activated protein kinase kinase 4 (MAP2K4), JNK3 [9].

There are two isoforms of Beta-arrestin, termed Beta-arrestin1 and 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 type-1-Beta-arrestin2-mediated ERK activation [13]. It has been shown that Beta-arrestin1 participates in internalization of the GPCR and binds to some elements of GPCR-mediated activation of MAPK [14], [15], [16].

References:

1. Goodfriend TL, Elliott ME, Catt KJ
   Angiotensin receptors and their antagonists. The New England journal of medicine 1996 Jun 20;334(25):1649-54
2. 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
3. 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
4. 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
5. 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
6. Pitcher JA, Freedman NJ, Lefkowitz RJ
   G protein-coupled receptor kinases. Annual review of biochemistry 1998;67:653-92
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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