Panther Pathway: P05911 The angiotensin 1a receptor mediates various angiotensin II (AngII)-dependent physiological responses such as vasoconstriction, smooth muscle cell motility and growth, and aldosterone secretion. By employing HEK-293 cells as a model system and utilizing b-arrestin and heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor kinase (GRK) RNAi technology, various novel aspects of angiotensin type II 1a receptor (AT1aR)-mediated extracellular signal-regulated protein kinase (ERK) activation have been uncovered. Stimulation of the receptor with its peptide ligand AngII results in the activation of Gaq/11 and the downstream kinase protein kinase C (PKC). This leads to the activation of the ERK cascade. The time course of this G protein-dependent ERK activation is rapid and transient, and the active ERK translocates to the nucleus to stimulate transcriptional pathways governed by Elk-1 activity and early growth response I (EGR-1) induction. The G protein-dependent ERK activation is not sensitive to b-arrestin RNAi and is eliminated by the addition of chemical inhibitors of PKC such as Ro-31-8425. The AngII-stimulated ERK pathway has an additional component that remains active for prolonged periods and is insensitive to PKC inhibitors. This pool of ERK is completely sensitive to b-arrestin 2 siRNA and remains excluded from the nucleus. b-arrestin 2-complexed ERK is targeted to endosomal compartments, where it presumably phosphorylates cytosolic substrates. Quite interestingly, b-arrestin 2-dependent ERK activation occurs only when b-arrestin 2 is recruited to GRK5- and/or GRK6- phosphorylated receptors. Depletion of cellular GRK5 or GRK6 isoforms results in complete inhibition of b-arrestin 2-dependent ERK activation, whereas depletion of the other GRK isoforms (GRK2 and 3) does not affect b-arrestin 2-dependent pERK, or rather even increases it. However, GRK2/3 are the primary kinases responsible for the bulk of receptor phosphorylation and overall b-arrestin recruitment to the receptor. Thus, the b-arrestin 2-dependent ERK pathway is associated with a specific b-arrestin 2 conformation induced by the GRK5/6-phosphorylated state of the receptor and not merely with b-arrestin recruitment to the receptor. Quite unexpectedly, b-arrestin 1 siRNA treatment enhances ERK activation elicited by b-arrestin 2-dependent mechanisms, suggesting that at physiological levels, b-arrestin 1 may act as a "dominant-negative" leading to inhibition of b-arrestin 2-dependent pERK. Whereas b-arrestin 2 can engage the ERK pathway independent of G proteins, b-arrestin 1 stimulates the small guanosine triphosphatase (GTPase) RhoA cooperatively with Gaq/11, leading to cytoskeletal changes and stress fiber formation. This pathway is adapted from the same pathway in STKE. Medline=12582207 Medline=12949261 Medline=14711824 Medline=15205453 Medline=15355986 Medline=15611106 Medline=15671181 Website=http://stke.sciencemag.org/cgi/cm/stkecm;CMP_16109 PMID: 12582207 PMID: 12949261 PMID: 14711824 PMID: 15205453 PMID: 15355986 PMID: 15611106 PMID: 15671181 4.0 Long Name: G-protein, beta subunit Synonym: Guanine nucleotide-binding protein, beta subunit Accession: P05930 s21 PROTEIN pr6 Long Name: G-protein, gamma subunit Synonym: Synonym not specified Accession: P05929 s21 PROTEIN pr7 Long Name: G-protein, beta subunit Synonym: Guanine nucleotide-binding protein, beta subunit Accession: P05930 s13 PROTEIN pr6 Long Name: G-protein, gamma subunit Synonym: Synonym not specified Accession: P05929 s13 PROTEIN pr7 Long Name: G-protein, beta subunit Synonym: Guanine nucleotide-binding protein, beta subunit Accession: P05930 s26 PROTEIN pr6 Long Name: G-protein, gamma subunit Synonym: Synonym not specified Accession: P05929 s26 PROTEIN pr7 Long Name: G-protein, alpha q subunit Synonym: Synonym not specified Accession: P05927 s13 PROTEIN pr5 Long Name: G-protein, alpha q subunit Synonym: Synonym not specified Accession: P05927 s21 PROTEIN pr5 Long Name: Angiotensin II Synonym: Synonym not specified Accession: P05935 s42 PROTEIN pr2 Long Name: G-protein, alpha q subunit Synonym: Synonym not specified Accession: P05927 s42 PROTEIN pr5 Long Name: G-protein, beta subunit Synonym: Guanine nucleotide-binding protein, beta subunit Accession: P05930 s42 PROTEIN pr6 Long Name: G-protein, gamma subunit Synonym: Synonym not specified Accession: P05929 s42 PROTEIN pr7 Long Name: Angiotensin II Synonym: Synonym not specified Accession: P05935 s36 PROTEIN pr2 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 s21 PROTEIN pr1 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 s42 PROTEIN pr1 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 s36 PROTEIN pr1 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 s94 PROTEIN pr1 Long Name: beta-arrestin 2 Synonym: ARB2,ARRB2 Accession: P05923 s94 PROTEIN pr12 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 s87 PROTEIN pr1 Long Name: beta-arrestin 2 Synonym: ARB2,ARRB2 Accession: P05923 s87 PROTEIN pr12 SQUARE SQUARE OVAL SQUARE inactive inactive inactive active inactive active active inactive inactive inactive active inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive inactive active inactive inactive inactive active inactive inactive active active inactive inactive inactive active active inactive inactive active inactive inactive inactive inactive active inactive inactive inactive active inactive inactive inactive active inactive active inactive active inactive active inactive active active inactive active inactive active inactive active inactive active inactive inactive active inactive active inactive SRI International cytosol ER nucleus endosome Long Name: Angiotensin II Synonym: Synonym not specified Accession: P05935 inside PROTEIN pr2 Long Name: G protein-coupled receptor kinase 6 Synonym: Synonym not specified Accession: P05939 inside PROTEIN pr3 Long Name: G protein-coupled receptor kinase 5 Synonym: Synonym not specified Accession: P05940 inside PROTEIN pr4 Long Name: G protein Synonym: Synonym not specified Accession: U06140 Heterodimer Member Info: Gqalpha#PROTEIN#G-protein, alpha q subunit#P05927##;Ggamma#PROTEIN#G-protein, gamma subunit#P05929##;Gbeta#PROTEIN#G-protein, beta subunit#P05930#Guanine nucleotide-binding protein, beta subunit# inside COMPLEX G protein Long Name: AT1R/G protein complex Synonym: Synonym not specified Accession: U06141 Heterodimer Member Info: AT1-R#PROTEIN#angiotensin type II 1a receptor#P05924#AGTR1|angiotensin receptor 1#;Gqalpha#PROTEIN#G-protein, alpha q subunit#P05927##;Ggamma#PROTEIN#G-protein, gamma subunit#P05929##;Gbeta#PROTEIN#G-protein, beta subunit#P05930#Guanine nucleotide-binding protein, beta subunit# transmembrane COMPLEX AT1R_slash_G protein_br_complex Long Name: Gbetagamma Synonym: Synonym not specified Accession: U06142 Heterodimer Member Info: Ggamma#PROTEIN#G-protein, gamma subunit#P05929##;Gbeta#PROTEIN#G-protein, beta subunit#P05930#Guanine nucleotide-binding protein, beta subunit# inside COMPLEX G_beta__gamma_ Long Name: G-protein, alpha q subunit Synonym: Synonym not specified Accession: P05927 inside PROTEIN pr5 Long Name: AngII/AT1-R complex Synonym: Synonym not specified Accession: U06143 Heterodimer Member Info: AT1-R#PROTEIN#angiotensin type II 1a receptor#P05924#AGTR1|angiotensin receptor 1#;AngII#PROTEIN#Angiotensin II#P05935## transmembrane COMPLEX AngII_slash_AT1_minus_R_br_complex Long Name: AngII/AT1-R G protein complex Synonym: Synonym not specified Accession: U06144 Heterodimer Member Info: AT1-R#PROTEIN#angiotensin type II 1a receptor#P05924#AGTR1|angiotensin receptor 1#;Gqalpha#PROTEIN#G-protein, alpha q subunit#P05927##;Ggamma#PROTEIN#G-protein, gamma subunit#P05929##;Gbeta#PROTEIN#G-protein, beta subunit#P05930#Guanine nucleotide-binding protein, beta subunit#;AngII#PROTEIN#Angiotensin II#P05935## transmembrane COMPLEX AngII_slash_AT1_minus_R_br_G protein_br_complex Long Name: G protein-coupled receptor kinase 3 Synonym: ADRBK2,BARK2,beta-adrenergic receptor kinase 2 Accession: P05941 inside PROTEIN pr8 Long Name: G protein-coupled receptor kinase 2 Synonym: ADRBK1,BARK1,beta-ARK1,beta-adrenergic receptor kinase 1 Accession: P05943 inside PROTEIN pr9 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 transmembrane PROTEIN pr1 Long Name: angiotensin type II 1a receptor Synonym: AGTR1,angiotensin receptor 1 Accession: P05924 transmembrane PROTEIN pr1 Long Name: PiP2 Synonym: Synonym not specified Accession: S06051 innerSurface SIMPLE_MOLECULE PiP2 Long Name: IP3 Synonym: Synonym not specified Accession: S06053 inside SIMPLE_MOLECULE IP3 Long Name: DAG Synonym: Synonym not specified Accession: S06052 inside SIMPLE_MOLECULE DAG Long Name: inositol 1,4,5-triphosphate receptor Synonym: Synonym not specified Accession: P05932 transmembrane PROTEIN pr13 Long Name: Ca2+ Synonym: Synonym not specified Accession: U06147 inside ION Ca_super_2+_endsuper_ Long Name: Ca2+ Synonym: Synonym not specified Accession: U06147 inside ION Ca_super_2+_endsuper_ Long Name: calcium release activated calcium channel Synonym: Synonym not specified Accession: P05936 transmembrane PROTEIN pr14 Long Name: protein kinase C Synonym: Synonym not specified Accession: P05942 inside PROTEIN pr15 Long Name: c-Raf-1 Synonym: MAPKKK Accession: P05928 inside PROTEIN pr16 Long Name: c-Raf-1 Synonym: MAPKKK Accession: P05928 inside PROTEIN pr16 Long Name: mitogen-activated or extracellular signal-regulated protein kinase Synonym: MAPKK,mitogen-activated protein kinase kinase Accession: P05926 inside PROTEIN pr17 Long Name: mitogen-activated or extracellular signal-regulated protein kinase Synonym: MAPKK,mitogen-activated protein kinase kinase Accession: P05926 inside PROTEIN pr17 Long Name: mitogen-activated protein kinase Synonym: ERK Accession: P05937 inside PROTEIN pr18 Long Name: ELK-1 member of EST oncogene family Synonym: Synonym not specified Accession: P05934 inside PROTEIN pr19 Long Name: mitogen-activated protein kinase Synonym: ERK Accession: P05937 inside PROTEIN pr18 Long Name: ELK-1 member of EST oncogene family Synonym: Synonym not specified Accession: P05934 inside PROTEIN pr19 Long Name: early growth response Synonym: KROX24,NGFIA Accession: P05931 inside PROTEIN pr20 Long Name: beta-arrestin 1 Synonym: ARB1,ARRB1 Accession: P05925 innerSurface PROTEIN pr11 Long Name: b-ArrAT1aR Synonym: Synonym not specified Accession: U06145 Heterodimer Member Info: beta-ARR2#PROTEIN#beta-arrestin 2#P05923#ARB2|ARRB2#;AT1-R#PROTEIN#angiotensin type II 1a receptor#P05924#AGTR1|angiotensin receptor 1# transmembrane COMPLEX b-ArrAT1aR Long Name: c-Raf-1 Synonym: MAPKKK Accession: P05928 inside PROTEIN pr16 Long Name: mitogen-activated or extracellular signal-regulated protein kinase Synonym: MAPKK,mitogen-activated protein kinase kinase Accession: P05926 inside PROTEIN pr17 Long Name: mitogen-activated or extracellular signal-regulated protein kinase Synonym: MAPKK,mitogen-activated protein kinase kinase Accession: P05926 inside PROTEIN pr17 Long Name: mitogen-activated protein kinase Synonym: ERK Accession: P05937 inside PROTEIN pr18 Long Name: mitogen-activated protein kinase Synonym: ERK Accession: P05937 inside PROTEIN pr18 Long Name: b-ArrAT1aR Synonym: Synonym not specified Accession: U06146 Heterodimer Member Info: beta-ARR2#PROTEIN#beta-arrestin 2#P05923#ARB2|ARRB2#;AT1-R#PROTEIN#angiotensin type II 1a receptor#P05924#AGTR1|angiotensin receptor 1# transmembrane COMPLEX b-ArrAT1aR Long Name: RhoA GTPase Synonym: ARHA Accession: P05938 inside PROTEIN pr22 Long Name: beta-arrestin 2 Synonym: ARB2,ARRB2 Accession: P05923 innerSurface PROTEIN pr12 Long Name: G protein-coupled receptor kinase 3 Synonym: ADRBK2,BARK2,beta-adrenergic receptor kinase 2 Accession: P05941 innerSurface PROTEIN pr8 Long Name: G protein-coupled receptor kinase 2 Synonym: ADRBK1,BARK1,beta-ARK1,beta-adrenergic receptor kinase 1 Accession: P05943 innerSurface PROTEIN pr9 Long Name: phospholipase C Synonym: Synonym not specified Accession: P05933 innerSurface PROTEIN pr10 HETERODIMER_ASSOCIATION 0.7357947106772751,0.3958674114147618 sa16 csa2 csa3 HETERODIMER_ASSOCIATION -0.18241113880060933,0.5445900820501324 sa2 csa3 csa1 sa5 sa6 DISSOCIATION 0.27223987671064975,-0.0065434206804071415 0.4796235461244793,0.0729212909526773 csa1 csa5 sa18 csa4 STATE_TRANSITION sa28 sa31 csa4 STATE_TRANSITION sa29 sa30 csa4 DISSOCIATION 0.1909000854247207,3.6074163325344744E-4 0.5711139443477284,0.26452781286241756 csa5 sa32 sa33 sa30 sa31 STATE_TRANSITION sa34 sa35 sa18 STATE_TRANSITION sa37 sa36 csa5 STATE_TRANSITION sa38 sa39 csa5 DISSOCIATION 0.2755205885994343,0.30137399106118856 sa40 sa42 sa41 sa35 STATE_TRANSITION sa43 sa44 sa41 STATE_TRANSITION 0.3526321344387915,-0.0015479694627797969 sa45 sa46 sa44 STATE_TRANSITION sa47 sa48 sa46 STATE_TRANSITION 0.26057726783792834,2.220446049250313E-15 sa50 sa49 sa48 STATE_TRANSITION 0.349009477449604,3.672821429789863E-4 sa51 sa52 sa49 sa42 STATE_TRANSITION sa53 sa54 sa52 STATE_TRANSITION sa55 sa57 sa54 STATE_TRANSITION sa58 sa59 sa57 STATE_TRANSITION sa60 sa61 sa59 STATE_TRANSITION sa66 sa67 csa6 STATE_TRANSITION sa68 sa69 sa67 STATE_TRANSITION sa70 sa71 sa69 HETERODIMER_ASSOCIATION 0.21086690097650518,0.6184329581383778 sa39 sa72 csa7 TRANSPORT csa7 csa6 STATE_TRANSITION sa75 sa78 sa36 sa18 STATE_TRANSITION sa79 sa62 sa61