MDM2, GRK6, ERK1 (MAPK3), cPKC (conventional), Clathrin, JNK3(MAPK10), MEK4(MAP2K4), MEK1(MAP2K1), Ubiquitin, c-Src, GRK3, Angiotensin II receptor, type-1, Ca(2+), Calmodulin, Beta-arrestin2, Angiotensin II, ERK2 (MAPK1), GRK5, GRK2, G-protein beta/gamma, Beta-adaptin 2, c-Raf-1, ASK1 (MAP3K5), PtdIns(4,5)P2, Beta-arrestin1
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 .
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 mechanisms .
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 GRK s 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 Beta-arrestin2/ MDM2 interaction 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 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 .
2) Apoptosis signal regulating kinase ( ASK1), Mitogen-activated protein kinase kinase 4 ( MAP2K4 ), JNK3 .
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 . It has been shown that Beta-arrestin1 participates in internalization of the GPCR and binds to some elements of GPCR-mediated activation of MAPK , , .