id: PW:0000528 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000528 title: angiotensin ii signaling pathway via at2 receptor description: Angiotensin II (AgtII), the product of Ace action in the renin-angiotensin pathway, is probably the most potent of the biologically active peptides the system generates. Overall AgtII elicits distinct responses through signaling via receptor type 1 and 2, Agtr1 and Agtr2, respectively. Signaling via receptor type 1 is by far the better understood system. The Agtr1 mediated pathway is involved in vasoconstriction, proliferation, hormone release and fluid homeostasis. The powerful but potentiallyharmful effects elicited by Agtr1 can be counterbalanced by the Agtr2 mediated signaling. The pathway mediated by receptor type 2 promotes vasodilation and natriuresis and exerts anti-inflammatory and anti-proliferative effects. It may also stimulate the production of nitric oxide (NO), cyclic GMP (cGMP) and bradykinin (not shown). Synthetic Agtr1 receptor antagonists, such as the frequently prescribed Losartan, are used as antihypertensive agents. Agtr2 can exert a comparable effect which may be overshadowed by the rather low level of expression the receptor has. Agtr2 is highly expressed in the fetus but declines abruptly in the neonatal period, except for a number of tissues. The receptor continues to be expressed in the adult kidney, heart, adrenal cortex and other specific sites including certain areas of the brain. Both receptors are seven transmembrane G-coupled protein (GPCR) receptors but the exhibit low sequence homology - 34%. They employ distinct heterotrimeric G proteins and both, particularly Agtr2, can elicit signals in the absence of G protein coupling. While the detailed molecular mechanisms of Agtr2 mediated signaling are still elusive, available data point to a number of aspects. The G protein coupled signaling engages the Gnai2 and 3 of the Galphai family. Activation of phosphotyrosine phosphatases proceeds in both a G protein- dependent and independent manner and leads to inhibition of the extracellular signal-regulated Raf/Mek/Erk MAP kinase signaling. For instance, activation of Dusp1 (known as Mkp-1) is G-protein dependent, whereas the activation of Ptpn6 (Known as Shp-1) is G-protein independent. The essential difference between Agtr1 and Agtr2 effects on this MAP kinase pathway may be one of the mechanisms thereby Agtr2 opposes some of Agrt1 actions. Several binding partners have been identified of which Mtus1, known as Atip1 is the best characterized and may be involved in receptor trafficking and intracellular signaling independent of coupling to heterotrimeric G proteins. Several transcripts have been identified for the human MTUS1 that results from alternative splicing and promoter usage. In addition to Mtus1, a number of other Agtr2 interacting partners have been identified that include Erbb3, Plzf, Cnk1, Nhe6, and Timp3 and which contact the same C-terminal intracellular region of the receptor. Overall, the Agtr2-protein interactions appear to confer a tumor suppressing function. diagram_image: https://rgd.mcw.edu/pathway/PW0000528/angiotensin%20II%20signaling%20pathway%20via%20AT2%20receptor/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000528/angiotensin%20II%20signaling%20pathway%20via%20AT2%20receptor/angiotensin%20II%20signaling%20pathway%20via%20AT2%20receptor.gpp diagram_pathway_links: - id: PW:0000102 label: the extracellular signal-regulated Raf/Mek/Erk signaling pathway - id: PW:0000228 label: G protein mediated signaling pathway via Galphai family - id: PW:0000492 label: renin-angiotensin cascade pathway diagram_gene_links: - id: RGD:2069 label: Agt - id: RGD:2072 label: Agtr2 - id: RGD:620897 label: Dusp1 - id: RGD:620243 label: Gnai2 - id: RGD:2714 label: Gnai3 - id: RGD:631381 label: Mtus1 - id: RGD:620660 label: Ptpn6 diagram_chemicals: - id: HMDB:HMDB01035 label: AgtII diagram_edges: - source: Agt relation: positively_affects target: AgtII - source: AgtII relation: associated_with target: Agtr2 - source: Agtr2 relation: associated_with target: Gnai2 - source: Agtr2 relation: associated_with target: Gnai3 - source: Agtr2 relation: associated_with target: Mtus1 - source: Agtr2 relation: associated_with target: other Agtr2 partners - source: Dusp1 relation: negatively_affects target: the extracellular signal-regulated Raf/Mek/Erk signaling pathway - source: Ptpn6 relation: negatively_affects target: the extracellular signal-regulated Raf/Mek/Erk signaling pathway diagram_labels: - AgtII independent effects - Agtr2 --+> AgtII independent effects - Agtr2 --+> Agtr2 mediated effects - Agtr2 --+> Dusp1 - Agtr2 --+> Ptpn6 - Agtr2 mediated effects - anti-inflammatory - anti-proliferative - G protein independent effects - natriuresis - vasodilation diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/other-agtr2-partners label: other Agtr2 partners references: - id: RGD:1581825 citation: de Gasparo M, etal., Pharmacol Rev. 2000 Sep;52(3):415-72. - id: RGD:5133675 citation: Jones ES, etal., Pharmacol Ther. 2008 Dec;120(3):292-316. Epub 2008 Aug 31. - id: RGD:5133677 citation: Steckelings UM, etal., Peptides. 2005 Aug;26(8):1401-9. Epub 2005 Apr 18. - id: RGD:5133679 citation: Rodrigues-Ferreira S and Nahmias C, Trends Endocrinol Metab. 2010 Nov;21(11):684-90. - id: RGD:7401256 citation: 'Padia SH and Carey RM, Pflugers Arch. 2013 Jan;465(1):99-110. doi: 10.1007/s00424-012-1146-3. Epub 2012 Sep 5.' - id: RGD:7411636 citation: 'McCarthy CA, etal., Curr Hypertens Rep. 2013 Feb;15(1):25-30. doi: 10.1007/s11906-012-0321-4.' - id: RGD:7411637 citation: 'Foulquier S, etal., Nature. 2013 Jan 31;493(7434):S9. doi: 10.1038/493S9a.' - id: RGD:7411638 citation: 'Horiuchi M, etal., Clin Sci (Lond). 2012 Aug 1;123(4):193-203. doi: 10.1042/CS20110677.' - id: RGD:7411639 citation: 'Mogi M and Horiuchi M, Geriatr Gerontol Int. 2013 Jan;13(1):13-8. doi: 10.1111/j.1447-0594.2012.00900.x. Epub 2012 Jun 21.'