| Predicate | Object |
|---|---|
| rdf:type | |
| biopax3:comment |
MODEL_NOTES=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
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Angiotensin_II-stimulated_signaling_through_G_proteins_and_beta-arrestin
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| biopax3:standardName |
Angiotensin_II-stimulated_signaling_through_G_proteins_and_beta-arrestin
|