id: MODULE:angiotensin_ii_receptor_signaling title: Angiotensin II receptor signaling — Ang II activation of AT1 (AGTR1) via Gq/11-PLC, JAK2/TYK2 and GRK/beta-arrestin desensitisation with AGTRAP/ARAP1 trafficking, versus AT2 (AGTR2) via Gi-linked SHP-1/MKP-1 phosphatases and MTUS1/ZBTB16 description: >- Angiotensin II (Ang II), the octapeptide released from angiotensinogen by the renin-angiotensin cascade, is the agonist of two seven-transmembrane G protein-coupled receptors with largely opposing actions: the type 1 receptor AT1 (AGTR1) and the type 2 receptor AT2 (AGTR2). The two receptors share only ~34% sequence identity and couple to different signalling machinery, so this module treats them as a variant set of receptor branches off a common ligand. AT1 is the dominant and best-understood receptor, expressed in most tissues and mediating vasoconstriction, aldosterone release, fluid homeostasis and cell proliferation. Agonist-occupied AT1 acts as a guanine-nucleotide exchange factor for the Gq/11 family (GNAQ, GNA11), whose GTP-bound alpha subunit activates phospholipase C beta to cleave PIP2 into IP3 and diacylglycerol, raising intracellular calcium and activating protein kinase C — the shared Gq-PLC-calcium-PKC effector cassette modelled elsewhere. AT1 also drives G protein-independent arms: it binds and activates the Janus kinases JAK2 and TYK2 to engage STAT transcription factors, and it is phosphorylated by G protein-coupled receptor kinases (GRK2, GRK3, GRK5, GRK6) so that the beta-arrestins ARRB1 and ARRB2 uncouple it from G proteins, carry it into clathrin-coated pits and scaffold an arrestin-dependent ERK signal. Receptor fate is tuned by two C-terminal-tail-binding proteins: AGTRAP (ATRAP), which promotes internalisation and dampens signalling, and ARAP1, which recycles the receptor back to the plasma membrane. The AT2 receptor couples instead to the inhibitory Gi alpha subunits (GNAI2, GNAI3) and, in both G protein-dependent and -independent ways, activates protein tyrosine phosphatases — SHP-1 (PTPN6) and the MAP-kinase phosphatase MKP-1 (DUSP1) — that inactivate the ERK MAP-kinase cascade, giving AT2 its antiproliferative, pro-apoptotic and vasodilatory character that counterbalances AT1. AT2 also signals through C-terminal-tail partners, best characterised being MTUS1 (ATIP) and the transcription factor ZBTB16 (PLZF). The upstream proteolytic generation of Ang II by renin, ACE and chymase is a separate pathway and is not modelled here. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000244 title: angiotensin II signaling pathway statement: >- The parent RGD Pathway Ontology term for Ang II signalling through both receptors. Its record states that "Agtr1 which is expressed in most tissues ... is the better understood system" mediating "vasoconstriction, proliferation, hormone release and fluid homeostasis" and that "The powerful but potentially harmful effects elicited by Agtr1 are counterbalanced by the Agtr2 mediated signaling", which "promotes vasodilation, NO release and growth inhibition". The RGD diagram draws AgtII associated with Agtr1a/Agtr1b and Agtr2, and links out to its two receptor subpathways PW:0000527 and PW:0000528, to the Galphaq (PW:0000229), Galphai (PW:0000228) and PKC (PW:0000840) G-protein subpathways, and to the renin-angiotensin cascade PW:0000492. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000244.yaml). Human genes RGD curates to PW:0000244: ACE AGT AGTR1 AGTR2 AGTRAP ARAP1 ARRB1 ARRB2 CCL2 CMA1 CNKSR1 DUSP1 ERBB3 GNA11 GNAI2 GNAI3 GNAQ GRK2 GRK3 GRK5 GRK6 JAK2 MTUS1 OLR1 PDPK1 PLA2G6 PRKCZ PTPN6 RGS2 SLC9A6 TIMP3 TYK2 ZBTB16. - source_id: PW:0000527 title: angiotensin II signaling pathway via AT1 receptor statement: >- The AT1 receptor branch of this module. RGD's PW:0000527 diagram draws Agtr1/Agtr1b associated with Gnaq and Gna11, with Agtrap, Arap1, Arrb1, Arrb2 and Jak2, with Rgs2 as a GAP on Gnaq/Gna11, and GRK members phosphorylating Agtr1; its labels trace Gnaq->IP3->Ca2+ and Gnaq->DAG into the PKC pathway and on to the Raf/Mek/Erk cascade, plus receptor internalization (Agtrap) and recycling (Arap1). RGD human genes: AGT AGTR1 AGTRAP ARAP1 ARRB1 ARRB2 GNA11 GNAQ GRK2 GRK3 GRK5 GRK6 JAK2 (plus RGS2 on the diagram). Derived through pathways/PW_0000527.yaml. - source_id: PW:0000528 title: angiotensin II signaling pathway via AT2 receptor statement: >- The AT2 receptor branch of this module. RGD's PW:0000528 diagram draws Agtr2 associated with Gnai2 and Gnai3 and with Mtus1 (and "other Agtr2 partners"), and shows Dusp1 and Ptpn6 negatively affecting the Raf/Mek/Erk cascade; the record text names "Mtus1, known as Atip1" as the best-characterised partner and lists "Erbb3, Plzf, Cnk1, Nhe6, and Timp3" among other partners contacting the same C-terminal region, conferring "a tumor suppressing function". RGD human genes: AGT AGTR2 CNKSR1 DUSP1 ERBB3 GNAI2 GNAI3 MTUS1 PTPN6 SLC9A6 TIMP3 ZBTB16. Derived through pathways/PW_0000528.yaml. - source_id: GO:0038166 title: angiotensin-activated signaling pathway statement: >- The GO biological-process term mapped to PW:0000244 (skos:closeMatch) and, more broadly, to the AT2 branch PW:0000528 (skos:broadMatch) in the project's curated mappings (projects/RGD_PATHWAY_ONTOLOGY/data/pw_go_curated.sssom.yaml). It is the module's process concept and is defined as the GPCR series of events initiated by angiotensin II binding its receptor. - source_id: GO:0086097 title: phospholipase C-activating angiotensin-activated signaling pathway statement: >- The GO process term mapped to the AT1 branch PW:0000527 (skos:closeMatch): AT1 (AGTR1) couples to Gq/11 and phospholipase C. It is a child of GO:0038166 and names the AT1 Gq-PLC arm of this module; AGTR1 carries it by IDA (PMID:1378723). - source_id: gomodel:6246724f00000549 title: Renin-angiotensin pathway (Human) statement: >- Human GO-CAM (cached under gocams/6246724f00000549/) and the best-overlap model for the shared ligand/receptor core. It models AGT hormone activity (GO:0005179) causally upstream of AGTR1 angiotensin type I receptor activity (GO:0001596), both part of GO:0038166 angiotensin-activated signaling pathway; the proteolytic steps (REN, ACE) in the same model belong to the excluded renin-angiotensin cascade. Grounds the AGT and AGTR1 annotons here. - source_id: gomodel:67f85f2b00004426 title: Desensitization of C5AR1-mediated signaling following phosphorylation by GRK2 or GRK3 (Human). statement: >- The RGD triage's lead GO-CAM for PW:0000244/PW:0000527 (overlap 4: GRK2, GRK3, ARRB1, ARRB2). It is a C5a-receptor model, not an angiotensin model, but it captures exactly the GRK->beta-arrestin desensitisation motif reused in the AT1 branch: GRK2 and GRK3 G protein-coupled receptor kinase activity (GO:0004703) and ARRB1/ARRB2 protein-macromolecule adaptor activity (GO:0030674), all part of GO:0002029 desensitization of G protein-coupled receptor signaling pathway. Grounds the GRK and beta-arrestin annotons by exemplar; the ligand/receptor it desensitises differs. - source_id: gomodel:6438950a00000766 title: Ubiquitination of WNK4 in the distal nephron by KLHL3 and its regulation by phosphorylation and dephosphorylation (Human) statement: >- Human GO-CAM in which AGT hormone activity (GO:0005179) is placed part_of GO:0038166 angiotensin-activated signaling pathway and drives PRKCA, the one model that types the AGT ligand against this module's process term rather than the renin-angiotensin one. - source_id: PMID:7746328 title: "Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor." statement: >- Establishes the AT1 JAK/STAT arm: Ang II activates and co-precipitates JAK2 (and TYK2) with the AT1 receptor. supporting_text: >- angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells - source_id: PMID:15671181 title: "Functional antagonism of different G protein-coupled receptor kinases for beta-arrestin-mediated angiotensin II receptor signaling." statement: >- For the AT1A receptor, GRK2/3 mediate receptor phosphorylation, beta-arrestin recruitment and endocytosis, while GRK5/6 are required for beta-arrestin-mediated ERK activation: the basis for keeping all four GRKs in the AT1 desensitisation step. supporting_text: >- Angiotensin II-stimulated receptor phosphorylation, beta-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3 - source_id: PMID:9230127 title: "Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase." statement: >- The AT2 receptor inhibits the ERK MAP-kinase cascade by functionally activating the SHP-1 (PTPN6) tyrosine phosphatase: the core of the AT2 phosphatase branch. supporting_text: >- Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors - source_id: PMID:9228085 title: "Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis." statement: >- The AT2 receptor activates MAP-kinase phosphatase-1 (MKP-1/DUSP1), inactivating ERK; the basis for including DUSP1 in the AT2 branch. supporting_text: >- The AT2 receptor inhibits MAP kinase activation, resulting in the inactivation of Bcl-2 and the induction of apoptosis notes: >- Derived from the RGD Pathway Ontology through the RGD_PATHWAY_ONTOLOGY project's diagram->module route, covering the parent angiotensin II signalling pathway PW:0000244 and both of its receptor subpathways, PW:0000527 (via AT1) and PW:0000528 (via AT2). All three are listed as evidence source_ids because the module genuinely covers each: the shared ligand/receptor core plus both receptor branches. The two branches are modelled as a variant set off a common ligand because AT1 and AT2 are distinct receptors (~34% identity) with different coupling and opposing physiology, exactly as RGD splits them. Boundary decisions. (1) BOUNDARY WITH THE RENIN-ANGIOTENSIN CASCADE (excluded). The proteolytic generation of the angiotensin peptides from angiotensinogen by renin (REN), ACE and chymase (CMA1) is the separate renin-angiotensin cascade pathway, PW:0000492, mapped to GO:0002003 angiotensin maturation in the project (skos:closeMatch). It is deliberately NOT modelled here and PW:0000492 is NOT an evidence source_id. ACE and CMA1 are on RGD's PW:0000244 gene list only as the enzymes that make the ligand; they do no receptor signalling and are left out. This follows the CLAUDE.md AGT worked example: a process under proteolysis (GO:0002003, is_a GO:0016486 peptide hormone processing) belongs to the cleaving enzyme, not to the substrate. (2) AGT AS THE LIGAND PRECURSOR (included, as ligand only). Applying the AGT worked example: AGT is not given a process role such as angiotensin maturation or vasoconstriction. The entity that signals is the Angiotensin-2 octapeptide (UniProtKB:P01019 PRO_0000032458, residues 25-32 of angiotensinogen), the agonist that binds AGTR1/AGTR2. GOA records this as AGT hormone activity (GO:0005179, IDA PMID:1567413) and the renin-angiotensin GO-CAM gomodel:6246724f00000549 models AGT hormone activity causally upstream of AGTR1 receptor activity; a second GO-CAM, gomodel:6438950a00000766, places AGT hormone activity part_of GO:0038166. So AGT appears here once, as the hormone (ligand) that feeds both receptor branches, exactly the single step it performs, mirroring how KNG1 is handled in modules/kallikrein_kinin_cascade.yaml. This is consistent with the AGT gene review, whose accepted core function is hormone activity GO:0005179 in GO:0038166. (3) THE Gq-PLC-CALCIUM-PKC EFFECTOR CASSETTE (by reference). AT1 coupling to Gq/11 (GNAQ, GNA11; both carry G protein activity GO:0003925 by IDA and PLC-activating GPCR signalling GO:0007200) activates PLC beta, IP3/calcium and PKC. The PLC-beta-downward steps are not re-modelled; they are included by module_ref to gpcr_plc_calcium_pkc_signaling#plc_beta_activation, which models PLC beta, IP3-receptor calcium release and conventional PKC. RGD draws this as the Gnaq->IP3/DAG->PKC arm linking to PW:0000229 (Galphaq), PW:0000840 (PKC), PW:0001139/PW:0001140 (calcium) and onward to the Raf/Mek/Erk cascade (PW:0000102); those PW ids are mentioned but are not evidence source_ids, since this module covers the receptor-proximal signalling, not those downstream modules. The ERK/MAPK cascade itself (modules/erk_cascade.yaml) and EGFR transactivation (modules/egfr_signaling.yaml, PW:0000170) are downstream neighbours, not parts. (4) RGS2 (context, not a part). RGS2 is drawn on the PW:0000527 diagram as a GAP that terminates Gq/11 signalling (GTPase activator activity GO:0005096, negative regulation of GPCR signalling GO:0045744; RGS2 gene review accepts GO:0005096 as core). It is the off-switch of the Gq arm that is itself modelled by reference, and RGS2 has no angiotensin-specific experimental GO annotation (its experimental rows are generic GAP activity); it is recorded as context here and belongs with the Gq effector module. It is mentioned in the PW:0000527 evidence statement but is not given its own annoton. (5) AT1 TRAFFICKING PARTNERS AGTRAP AND ARAP1 (included). Both bind the AT1 C-terminal tail and set receptor fate in opposite directions — AGTRAP (ATRAP) promotes internalisation and inhibits signalling (PMID:10358057, PMID:11162453), ARAP1 recycles the receptor to the surface (PMID:14559250) — so they are genuine regulatory parts of the AT1 branch, not downstream biology. AGTRAP's function here is its AT1-tail binding (type 1 angiotensin receptor binding GO:0031702), the activity its gene review proposes as core; its only experimental MF row in human GOA is bare protein binding, which is not used. ARAP1's modelled activity is its experimental Arf-GAP activity (GTPase activator activity GO:0005096, IDA) acting in receptor recycling (GO:0001881). (6) AT2 PARTNERS. GNAI2/GNAI3 are the Gi alpha subunits AT2 couples to (PMID:8663053; GNAI2 gene review accepts G protein activity GO:0003925 as core; GNAI3 carries adenylate cyclase-inhibiting GPCR signalling GO:0007193 by IDA). PTPN6 (SHP-1) and DUSP1 (MKP-1) are the phosphatases that execute AT2's ERK inhibition (PMID:9230127, PMID:10406457, PMID:9228085); PTPN6's modelled activity is its experimental non-membrane spanning protein tyrosine phosphatase activity (GO:0004726, its gene-review core), DUSP1's is MAP kinase tyrosine/serine/threonine phosphatase activity (GO:0017017). MTUS1 (ATIP1) is the best-characterised AT2 C-terminal partner (PMID:15123706) but has no experimental molecular function beyond protein binding, so it is modelled as a participant with a role description and no function term (GO:0005515 protein binding is not used as a function). ZBTB16 (PLZF) is the AT2-binding transcription factor that routes to p85 PI3K and cardiac hypertrophy (PMID:14657020, PMID:22558183); its modelled activity is its experimental DNA-binding transcription repressor activity (GO:0001227). (7) AT2 PARTNERS AND OUTPUTS LEFT OUT. CNKSR1 (CNK1), ERBB3, SLC9A6 (NHE6) and TIMP3 are named in the PW:0000528 record text as further AT2 C-terminal-tail partners, but each has only a reported binding or an activity (ERBB3 neuregulin co-receptor; TIMP3 metalloproteinase inhibitor; SLC9A6 endosomal Na+/H+ exchanger; CNKSR1 scaffold) whose role in AT2 signalling is not established by angiotensin-specific experimental evidence and is not in any cached GO-CAM; they are recorded as candidate partners to revisit, not participants. ERBB3 is better placed as the trans-inactivated receptor tyrosine kinase (the object AT2 acts against), not a carrier of the AT2 signal. CCL2 (MCP-1), OLR1 (LOX-1), PLA2G6, PDPK1 and PRKCZ are on RGD's PW:0000244 list as downstream or contextual effectors (chemokine output, oxidised-LDL receptor, calcium-independent phospholipase, PDK1/atypical-PKC arm) rather than receptor-proximal signalling; by the substrate-vs-participant and comparator reasoning they are outputs/context and are left for the downstream modules, not modelled here. Molecular functions were taken from each protein's experimental GO annotations in QuickGO (October 2026) and, where a gene review exists, from its accepted core functions: AGT hormone activity GO:0005179 (IDA, core in the AGT review); AGTR1 angiotensin type I receptor activity GO:0001596 (IDA, multiple); GNAQ/GNA11 G protein activity GO:0003925 (IDA; core in both reviews); JAK2 and TYK2 non-membrane spanning protein tyrosine kinase activity GO:0004715 (IDA for both); GRK2/GRK3/GRK6 G protein-coupled receptor kinase activity GO:0004703 (IDA; GRK2 core in its review); GRK5 is retained in the GRK variant set although its experimental rows are protein serine/threonine and beta-adrenergic receptor kinase activity; ARRB1/ARRB2 protein-macromolecule adaptor activity GO:0030674 (IDA, as in the C5AR1 GO-CAM); AGTRAP type 1 angiotensin receptor binding GO:0031702 (AGTRAP review core); ARAP1 GTPase activator activity GO:0005096 (IDA); AGTR2 angiotensin type II receptor activity GO:0004945 (IDA, multiple); GNAI2 G protein activity GO:0003925 (core in its review); PTPN6 non-membrane spanning protein tyrosine phosphatase activity GO:0004726 (review core); DUSP1 MAP kinase tyrosine/serine/threonine phosphatase activity GO:0017017; ZBTB16 DNA-binding transcription repressor activity GO:0001227 (IDA). No PANTHER family or PTN ids are asserted. GO-CAM observations for upstream review. The RGD triage's lead model for PW:0000244, gomodel:67f85f2b00004426, is a C5a-receptor (C5AR1) desensitisation model, not an angiotensin model; the four-gene overlap (GRK2/GRK3/ARRB1/ARRB2) reflects the shared desensitisation machinery, and it grounds the AT1 GRK/arrestin step only by mechanistic exemplar. There is no cached production GO-CAM of the AT1 JAK/STAT arm, of the AT2 receptor branch, or of AGTR2 enabling angiotensin type II receptor activity, although AGTR2 carries GO:0004945 by IDA in human; these are gaps worth a dedicated angiotensin-receptor GO-CAM. Gene reviews exist for AGT, AGTRAP, GNAQ, GNA11, GNAI2, GRK2, GRK5, PTPN6 and RGS2; AGTR1, AGTR2, ARRB1, ARRB2, ARAP1, GRK3, GRK6, JAK2, TYK2, GNAI3, DUSP1, MTUS1 and ZBTB16 have no gene review yet. module: id: angiotensin_ii_receptor_signaling label: Angiotensin II receptor signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: angiotensin-activated signaling pathway term: id: GO:0038166 label: angiotensin-activated signaling pathway description: >- GPCR signalling initiated by angiotensin II binding its receptor. The GO term mapped to PW:0000244 (closeMatch) and the AT2 branch PW:0000528 (broadMatch). context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: Angiotensin II peptide as the shared receptor ligand node: id: angiotensin_ii_ligand label: Angiotensin II (cleaved from angiotensinogen) acting as a hormone on AT1 and AT2 module_type: REGULATORY_STEP description: >- The Angiotensin-2 octapeptide, cleaved from angiotensinogen (AGT) by the renin-angiotensin cascade (modelled separately), is the agonist that binds and activates both receptors. Only this ligand step is attributed to AGT; the proteolysis that produces it belongs to the enzymes of PW:0000492. annotons: - id: agt_hormone label: Angiotensin II hormone (receptor ligand) activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGT (Angiotensin-2 peptide) term: id: UniProtKB:P01019 label: Angiotensinogen function: preferred_term: hormone activity term: id: GO:0005179 label: hormone activity targets: - preferred_term: AGTR1 (AT1 receptor) term: id: UniProtKB:P30556 label: Type-1 angiotensin II receptor - preferred_term: AGTR2 (AT2 receptor) term: id: UniProtKB:P50052 label: Type-2 angiotensin II receptor locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- The active species is the Angiotensin-2 cleavage product (UniProtKB:P01019 PRO_0000032458); it acts as a circulating/local hormone agonist of both AT1 and AT2. AGT performs no step of the pathway other than being the ligand. evidence: - source_id: PMID:1567413 statement: The cloned human AT1 receptor binds angiotensin II and couples to calcium mobilization. supporting_text: mobilization of intracellular stores of calcium gocam_associations: - model: gomodel:6246724f00000549 activity: gomodel:6246724f00000549/6246724f00000571 title: AGT hormone activity (GO:0005179), part of GO:0002034, upstream of AGTR1 - model: gomodel:6438950a00000766 activity: gomodel:6438950a00000766/6438950a00000826 title: AGT hormone activity (GO:0005179), part of GO:0038166 angiotensin-activated signaling pathway variant_sets: - id: angiotensin_receptor_branches label: Angiotensin II receptor branches (AT1 versus AT2) axis: receptor paralog selection: ONE_OR_MORE notes: >- The two receptors are distinct gene products with opposing physiology and different coupling. AT1 (AGTR1) is the dominant Gq/PLC-coupled receptor that also signals through JAK/STAT and beta-arrestin and is trafficked by AGTRAP/ARAP1; AT2 (AGTR2) couples to Gi and activates ERK-inactivating phosphatases, opposing AT1. Either (or both) branch satisfies the module. RGD splits them into PW:0000527 and PW:0000528. variants: - id: at1_branch label: AT1 (AGTR1) receptor branch module_type: SIGNALING_PATHWAY description: >- Ang II activation of AGTR1 and its Gq/11-PLC, JAK/STAT and GRK/beta-arrestin arms, with AGTRAP/ARAP1 setting receptor fate. Covers RGD PW:0000527. concepts: - preferred_term: phospholipase C-activating angiotensin-activated signaling pathway term: id: GO:0086097 label: phospholipase C-activating angiotensin-activated signaling pathway description: The GO process mapped to PW:0000527; AGTR1 carries it by IDA (PMID:1378723). parts: - order: 1 role: AT1 receptor activation by angiotensin II node: id: at1_receptor_activation label: AGTR1 angiotensin type I receptor activity module_type: REGULATORY_STEP description: >- Agonist-occupied AT1 is a GPCR that, as a GEF, activates heterotrimeric Gq/11 (and can engage other effectors and signal G protein-independently). annotons: - id: agtr1_receptor label: AGTR1 (AT1) angiotensin type I receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGTR1 term: id: UniProtKB:P30556 label: Type-1 angiotensin II receptor function: preferred_term: angiotensin type I receptor activity term: id: GO:0001596 label: angiotensin type I receptor activity processes: - preferred_term: phospholipase C-activating angiotensin-activated signaling pathway term: id: GO:0086097 label: phospholipase C-activating angiotensin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The dominant, widely expressed Ang II receptor; mediates vasoconstriction, aldosterone release, proliferation and fluid homeostasis. evidence: - source_id: PMID:1378723 statement: The cloned human AT1A receptor binds Ang II and is functionally coupled to inositol phosphate (PLC) signalling. supporting_text: functionally coupled to inositol phosphate turnover - source_id: PMID:25913193 statement: AT1R is the primary regulator of blood pressure, a GPCR whose structure was solved with an antagonist. supporting_text: Angiotensin II type 1 receptor gocam_associations: - model: gomodel:6246724f00000549 activity: gomodel:6246724f00000549/6246724f00000580 title: AGTR1 angiotensin type I receptor activity (GO:0001596), part of GO:0038166 - order: 2 role: Gq/11 coupling to the PLC-calcium-PKC effector cassette node: id: at1_gq_coupling label: AT1 activates Gq/11 (GNAQ/GNA11) module_type: REGULATORY_STEP description: >- AT1 acts as a GEF for the Gq/11 alpha subunits GNAQ and GNA11; GTP-bound Gq/11 activates phospholipase C beta. annotons: - id: gnaq_switch label: GNAQ G protein activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAQ term: id: UniProtKB:P50148 label: Guanine nucleotide-binding protein G(q) subunit alpha function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: GTP-bound Gq alpha that activates PLC beta downstream of AT1. - id: gna11_switch label: GNA11 G protein activity (redundant with GNAQ) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNA11 term: id: UniProtKB:P29992 label: Guanine nucleotide-binding protein subunit alpha-11 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: phospholipase C-activating G protein-coupled receptor signaling pathway term: id: GO:0007200 label: phospholipase C-activating G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: The Gq-family paralog partly redundant with GNAQ; RGD draws both on Agtr1. - order: 3 role: PLC beta / IP3-calcium / DAG-PKC effector cascade (shared module) node: id: at1_plc_effector label: PLC beta, IP3/calcium and DAG/PKC (by reference) description: >- Included by reference to the PLC beta step of the generic Gq-PLC-calcium-PKC module; its downstream IP3-receptor calcium release and conventional-PKC steps are in the same referenced module. module_ref: gpcr_plc_calcium_pkc_signaling#plc_beta_activation - order: 4 role: AT1 G protein-independent JAK/STAT arm node: id: at1_jak_stat label: AT1 activation of JAK2/TYK2 and STAT phosphorylation module_type: REGULATORY_STEP description: >- Ang II stimulation leads AT1 to bind and activate the Janus kinases JAK2 and TYK2, which tyrosine-phosphorylate STAT transcription factors; JAK2 co-precipitates with the receptor. This arm can proceed independently of G protein coupling. concepts: - preferred_term: cell surface receptor signaling pathway via JAK-STAT term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT annotons: - id: jak2_kinase label: JAK2 non-receptor tyrosine kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: JAK2 term: id: UniProtKB:O60674 label: Tyrosine-protein kinase JAK2 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity processes: - preferred_term: cell surface receptor signaling pathway via JAK-STAT term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: The principal AT1-associated Janus kinase; phosphorylates STAT1/STAT2. evidence: - source_id: PMID:7746328 statement: Ang II activates JAK2 (and TYK2) and JAK2 co-precipitates with AT1. supporting_text: >- Jak2 co-precipitates with the AT1 receptor, indicating that G-protein-coupled receptors may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors - id: tyk2_kinase label: TYK2 non-receptor tyrosine kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: TYK2 term: id: UniProtKB:P29597 label: Non-receptor tyrosine-protein kinase TYK2 function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity processes: - preferred_term: cell surface receptor signaling pathway via JAK-STAT term: id: GO:0007259 label: cell surface receptor signaling pathway via JAK-STAT locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: The second Janus kinase tyrosine-phosphorylated in response to Ang II via AT1. evidence: - source_id: PMID:7746328 statement: Ang II rapidly phosphorylates JAK2 and TYK2 in vascular smooth muscle cells. supporting_text: >- angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells - order: 5 role: GRK phosphorylation and beta-arrestin desensitisation / internalisation node: id: at1_grk_arrestin label: GRK/beta-arrestin desensitisation and internalisation of AT1 module_type: REGULATORY_STEP description: >- Agonist-occupied AT1 is phosphorylated by G protein-coupled receptor kinases; beta-arrestins ARRB1/ARRB2 then bind the phosphorylated receptor, uncouple it from G proteins, drive clathrin-mediated internalisation and scaffold an arrestin-dependent ERK signal. GRK2/3 drive phosphorylation and endocytosis; GRK5/6 enable the arrestin-dependent ERK signal. concepts: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway annotons: - id: grk2_kinase label: GRK2 G protein-coupled receptor kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK2 term: id: UniProtKB:P25098 label: Beta-adrenergic receptor kinase 1 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- The main GRK phosphorylating agonist-occupied AT1; GRK2/3 drive receptor phosphorylation, arrestin recruitment and endocytosis. evidence: - source_id: PMID:15671181 statement: GRK2/3 mediate AT1A phosphorylation, beta-arrestin recruitment and endocytosis. supporting_text: >- Angiotensin II-stimulated receptor phosphorylation, beta-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3 gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004469 title: GRK2 G protein-coupled receptor kinase activity (GO:0004703), part of GO:0002029 (C5AR1 exemplar) - id: arrb1_adaptor label: ARRB1 (beta-arrestin-1) adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ARRB1 term: id: UniProtKB:P49407 label: Beta-arrestin-1 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway - preferred_term: G protein-coupled receptor internalization term: id: GO:0002031 label: G protein-coupled receptor internalization locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- Binds GRK-phosphorylated AT1, desensitises G protein coupling, drives internalisation and (with Gq/11) scaffolds RhoA/ERK signalling. evidence: - source_id: PMID:15611106 statement: beta-arrestin 1 is required with Gq/11 for AT1A-directed RhoA activation. supporting_text: beta-arrestin 1 is required to activate the small GTPase RhoA gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004504 title: ARRB1 protein-macromolecule adaptor activity (GO:0030674), part of GO:0002029 (C5AR1 exemplar) - id: arrb2_adaptor label: ARRB2 (beta-arrestin-2) adaptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ARRB2 term: id: UniProtKB:P32121 label: Beta-arrestin-2 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway - preferred_term: G protein-coupled receptor internalization term: id: GO:0002031 label: G protein-coupled receptor internalization locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- Partly redundant with ARRB1; depletion of beta-arrestins reduces AT1 internalisation and arrestin-dependent ERK. evidence: - source_id: PMID:12582207 statement: beta-arrestin depletion reduces angiotensin II receptor internalisation and arrestin-dependent ERK. supporting_text: >- angiotensin II receptor internalization and impaired activation of the MAP kinases ERK 1 and 2 by angiotensin II gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004511 title: ARRB2 protein-macromolecule adaptor activity (GO:0030674), part of GO:0002029 (C5AR1 exemplar) variant_sets: - id: additional_at1_grks label: Additional GRKs acting on AT1 axis: GRK paralog selection: ONE_OR_MORE notes: >- RGD draws "GRK members" phosphorylating Agtr1; GRK3 behaves like GRK2, while GRK5 and GRK6 are specifically required for beta-arrestin-mediated ERK activation downstream of AT1 (PMID:15671181). GRK5's experimental MF rows are protein serine/threonine and beta-adrenergic receptor kinase activity. variants: - id: grk3_variant label: GRK3 module_type: REGULATORY_STEP annotons: - id: grk3_kinase label: GRK3 G protein-coupled receptor kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK3 term: id: UniProtKB:P35626 label: G protein-coupled receptor kinase 3 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway role_description: Behaves with GRK2 in AT1 phosphorylation and endocytosis. gocam_associations: - model: gomodel:67f85f2b00004426 activity: gomodel:67f85f2b00004426/67f85f2b00004492 title: GRK3 G protein-coupled receptor kinase activity (GO:0004703), part of GO:0002029 (C5AR1 exemplar) - id: grk6_variant label: GRK6 module_type: REGULATORY_STEP annotons: - id: grk6_kinase label: GRK6 G protein-coupled receptor kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK6 term: id: UniProtKB:P43250 label: G protein-coupled receptor kinase 6 function: preferred_term: G protein-coupled receptor kinase activity term: id: GO:0004703 label: G protein-coupled receptor kinase activity processes: - preferred_term: desensitization of G protein-coupled receptor signaling pathway term: id: GO:0002029 label: desensitization of G protein-coupled receptor signaling pathway role_description: >- GRK5/6-class kinase required for beta-arrestin-mediated ERK activation downstream of AT1. evidence: - source_id: PMID:15671181 statement: GRK5/6 are required for beta-arrestin-mediated ERK downstream of AT1, opposite to GRK2/3. supporting_text: >- inhibiting GRK 5 or 6 expression abolishes beta-arrestin-mediated ERK activation, whereas lowering GRK 2 or 3 leads to an increase in this signaling - id: grk5_variant label: GRK5 module_type: REGULATORY_STEP annotons: - id: grk5_kinase label: GRK5 protein serine/threonine kinase activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GRK5 term: id: UniProtKB:P34947 label: G protein-coupled receptor kinase 5 function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity processes: - preferred_term: regulation of G protein-coupled receptor signaling pathway term: id: GO:0008277 label: regulation of G protein-coupled receptor signaling pathway role_description: >- GRK5/6-class receptor kinase required with GRK6 for beta-arrestin-mediated ERK downstream of AT1 (its experimental MF rows are Ser/Thr and beta-adrenergic receptor kinase activity). - order: 6 role: AT1 trafficking by tail-binding partners AGTRAP and ARAP1 node: id: at1_trafficking label: AGTRAP-driven internalisation and ARAP1-driven recycling of AT1 module_type: REGULATORY_STEP description: >- Two proteins binding the AT1 C-terminal tail set receptor fate in opposite directions: AGTRAP (ATRAP) promotes internalisation and dampens signalling, ARAP1 recycles internalised receptor back to the plasma membrane. annotons: - id: agtrap_binding label: AGTRAP (ATRAP) AT1 receptor binding participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGTRAP term: id: UniProtKB:Q6RW13 label: Type-1 angiotensin II receptor-associated protein function: preferred_term: type 1 angiotensin receptor binding term: id: GO:0031702 label: type 1 angiotensin receptor binding processes: - preferred_term: positive regulation of receptor internalization term: id: GO:0002092 label: positive regulation of receptor internalization - preferred_term: negative regulation of angiotensin-activated signaling pathway term: id: GO:0110062 label: negative regulation of angiotensin-activated signaling pathway locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- Binds the AT1 C-terminal tail, enhances internalisation and inhibits AT1-mediated PLC signalling and proliferation. evidence: - source_id: PMID:10358057 statement: ATRAP binds the AT1a C-terminal tail and inhibits AT1a-mediated PLC activation. supporting_text: >- Overexpression of ATRAP in COS-7 cells caused a marked inhibition of AT1a receptor-mediated activation of phospholipase C - source_id: PMID:11162453 statement: ATRAP potentiates AT1 receptor internalisation on Ang II stimulation. supporting_text: >- Transfection of ATRAP potentiated AT1 receptor internalization upon Ang II stimulation in these VSMCs - id: arap1_recycling label: ARAP1 GTPase activator activity in AT1 recycling participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ARAP1 term: id: UniProtKB:Q96P48 label: Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 1 function: preferred_term: GTPase activator activity term: id: GO:0005096 label: GTPase activator activity processes: - preferred_term: receptor recycling term: id: GO:0001881 label: receptor recycling locations: - preferred_term: recycling endosome membrane term: id: GO:0055038 label: recycling endosome membrane role_description: >- Binds the AT1 tail and recycles internalised receptor to the plasma membrane, restoring responsiveness; an Arf/Rho-GAP (GTPase activator). evidence: - source_id: PMID:14559250 statement: ARAP1 binds AT1A and promotes its recycling to the plasma membrane. supporting_text: >- we report the isolation of a novel protein, ARAP1, which promotes recycling of AT(1A) to the plasma membrane in HEK-293 cells connections: - source: at1_receptor_activation target: at1_gq_coupling connection_type: CAUSES description: Agonist-occupied AT1 acts as a GEF activating Gq/11. - source: at1_gq_coupling target: at1_plc_effector connection_type: CAUSES description: GTP-bound Gq/11 activates PLC beta (shared effector module). - source: at1_receptor_activation target: at1_jak_stat connection_type: CAUSES description: AT1 binds and activates JAK2/TYK2, a G protein-independent arm. - source: at1_receptor_activation target: at1_grk_arrestin connection_type: PROVIDES_INPUT_FOR description: >- Agonist-occupied AT1 is the GRK substrate; GRK-phosphorylated receptor recruits beta-arrestins. - source: at1_grk_arrestin target: at1_receptor_activation connection_type: NEGATIVELY_REGULATES description: >- beta-arrestin binding desensitises AT1 G protein coupling and internalises the receptor, the branch's off-switch. - source: at1_grk_arrestin target: at1_trafficking connection_type: PROVIDES_INPUT_FOR description: Internalised AT1 is handled by AGTRAP/ARAP1 trafficking. - id: at2_branch label: AT2 (AGTR2) receptor branch module_type: SIGNALING_PATHWAY description: >- Ang II activation of AGTR2, coupling to Gi (GNAI2/GNAI3) and activation of ERK-inactivating phosphatases (SHP-1/PTPN6, MKP-1/DUSP1), with the tail-binding partners MTUS1 and ZBTB16. Opposes AT1. Covers RGD PW:0000528 (broadMatch to GO:0038166; GO has no AT2-specific term). parts: - order: 1 role: AT2 receptor activation and Gi coupling node: id: at2_receptor_activation label: AGTR2 angiotensin type II receptor activity and Gi coupling module_type: REGULATORY_STEP description: >- Ang II activates AT2, which couples to the inhibitory Gi alpha subunits GNAI2 and GNAI3. AT2 signalling also proceeds G protein-independently; a non-canonical helix VIII in AT2 structures limits G protein/arrestin recruitment. annotons: - id: agtr2_receptor label: AGTR2 (AT2) angiotensin type II receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AGTR2 term: id: UniProtKB:P50052 label: Type-2 angiotensin II receptor function: preferred_term: angiotensin type II receptor activity term: id: GO:0004945 label: angiotensin type II receptor activity processes: - preferred_term: angiotensin-activated signaling pathway term: id: GO:0038166 label: angiotensin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The counter-regulatory Ang II receptor; antiproliferative, pro-apoptotic and vasodilatory, opposing AT1. evidence: - source_id: PMID:28379944 statement: The AT2 structure shows a non-canonical helix VIII that prevents G protein/arrestin recruitment, matching its weak signalling in standard assays. supporting_text: >- preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard - id: gnai2_switch label: GNAI2 G protein activity (Gi coupling) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAI2 term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway term: id: GO:0007193 label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- One of the Gi alpha subunits AT2 couples to in the fetus (with GNAI3); the inhibitory G protein of the branch. evidence: - source_id: PMID:8663053 statement: The AT2 receptor couples to Gialpha2 and Gialpha3. supporting_text: AT2 receptor couples to both Gialpha2 and Gialpha3 - id: gnai3_switch label: GNAI3 G protein activity (Gi coupling, redundant with GNAI2) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: GNAI3 term: id: UniProtKB:P08754 label: Guanine nucleotide-binding protein G(i) subunit alpha-3 function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway term: id: GO:0007193 label: adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: The second Gi alpha subunit co-immunoselected with AT2 (PMID:8663053). - order: 2 role: AT2 activation of ERK-inactivating protein phosphatases node: id: at2_phosphatase_arm label: SHP-1 (PTPN6) and MKP-1 (DUSP1) inactivation of the ERK cascade module_type: REGULATORY_STEP description: >- AT2 activates protein tyrosine phosphatases that inactivate the ERK MAP kinase cascade: SHP-1 (PTPN6), a proximal AT2 effector activated in a G protein-independent manner, and MKP-1 (DUSP1), activated G protein-dependently. The net effect is dephosphorylation of ERK and the antiproliferative/pro-apoptotic AT2 phenotype. concepts: - preferred_term: negative regulation of ERK1 and ERK2 cascade term: id: GO:0070373 label: negative regulation of ERK1 and ERK2 cascade annotons: - id: ptpn6_phosphatase label: PTPN6 (SHP-1) tyrosine phosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTPN6 term: id: UniProtKB:P29350 label: Tyrosine-protein phosphatase non-receptor type 6 function: preferred_term: non-membrane spanning protein tyrosine phosphatase activity term: id: GO:0004726 label: non-membrane spanning protein tyrosine phosphatase activity processes: - preferred_term: negative regulation of ERK1 and ERK2 cascade term: id: GO:0070373 label: negative regulation of ERK1 and ERK2 cascade locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- A proximal AT2 effector: Ang II activates SHP-1 catalytic activity to inhibit ERK and trigger growth inhibition/apoptosis. evidence: - source_id: PMID:9230127 statement: AT2 stimulation activates SHP-1 and inhibits the ERK MAP-kinase cascade. supporting_text: >- Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors - source_id: PMID:10406457 statement: Preventing SHP-1 activation blocks AT2-induced ERK inhibition and apoptosis. supporting_text: >- preventing SHP-1 activation strongly attenuates AT2-induced ERK inhibition and apoptosis - id: dusp1_phosphatase label: DUSP1 (MKP-1) MAP kinase phosphatase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DUSP1 term: id: UniProtKB:P28562 label: Dual specificity protein phosphatase 1 function: preferred_term: MAP kinase tyrosine/serine/threonine phosphatase activity term: id: GO:0017017 label: MAP kinase tyrosine/serine/threonine phosphatase activity processes: - preferred_term: negative regulation of ERK1 and ERK2 cascade term: id: GO:0070373 label: negative regulation of ERK1 and ERK2 cascade locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- MAP-kinase phosphatase activated downstream of AT2; dephosphorylates/ inactivates ERK, dephosphorylating Bcl-2 and promoting apoptosis. evidence: - source_id: PMID:9228085 statement: AT2 activates MKP-1 (DUSP1) to inactivate ERK and induce apoptosis. supporting_text: >- The AT2 receptor inhibits MAP kinase activation, resulting in the inactivation of Bcl-2 and the induction of apoptosis - order: 3 role: AT2 C-terminal-tail partners MTUS1 and ZBTB16 node: id: at2_tail_partners label: MTUS1 (ATIP) and ZBTB16 (PLZF) AT2 interacting partners module_type: REGULATORY_STEP description: >- AT2 signals through proteins that bind its C-terminal tail. MTUS1 (ATIP1) transmits growth-inhibitory, G protein-independent signals; ZBTB16 (PLZF) is recruited to the AT2 tail, moves to the nucleus and drives a p85-PI3K transcriptional programme linked to cardiac hypertrophy. annotons: - id: mtus1_partner label: MTUS1 (ATIP1) AT2-interacting partner participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MTUS1 term: id: UniProtKB:Q9ULD2 label: Microtubule-associated tumor suppressor 1 role_description: >- The best-characterised AT2 C-terminal-tail partner; transmits growth-inhibitory signals and trans-inactivates receptor tyrosine kinases, independently of G protein coupling. No experimental molecular function beyond protein binding is available, so no function term is asserted. evidence: - source_id: PMID:15123706 statement: ATIP (MTUS1) binds the AT2 C-terminal tail and cooperates with AT2 to inhibit receptor tyrosine kinase signalling. supporting_text: >- ATIP1 cooperates with AT2 to transinactivate receptor tyrosine kinases - id: zbtb16_partner label: ZBTB16 (PLZF) AT2-recruited transcription repressor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ZBTB16 term: id: UniProtKB:Q05516 label: Zinc finger and BTB domain-containing protein 16 function: preferred_term: DNA-binding transcription repressor activity, RNA polymerase II-specific term: id: GO:0001227 label: DNA-binding transcription repressor activity, RNA polymerase II-specific locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Recruited to the AT2 C-terminal tail on Ang II stimulation; relocates to the nucleus and, binding the p85-alpha PI3K gene, drives a transcriptional programme behind the AT2 cardiac hypertrophic response. evidence: - source_id: PMID:14657020 statement: The AT2 C-terminus binds the transcription factor PLZF, which then upregulates p85 PI3K. supporting_text: >- AT 2 C-terminus binds to the transcription factor promyelocytic zinc finger protein (PLZF) - source_id: PMID:22558183 statement: PLZF is the AT2-binding protein mediating Ang II-induced cardiac hypertrophy, acting on GATA4. supporting_text: >- PLZF is an important AT(2) receptor binding protein in mediating Ang II induced cardiac hypertrophy connections: - source: at2_receptor_activation target: at2_phosphatase_arm connection_type: POSITIVELY_REGULATES description: AT2 activates SHP-1 and MKP-1 to inactivate the ERK cascade. - source: at2_receptor_activation target: at2_tail_partners connection_type: PROVIDES_INPUT_FOR description: The AT2 C-terminal tail recruits MTUS1 and ZBTB16. connections: - source: angiotensin_ii_ligand target: angiotensin_receptor_branches connection_type: PROVIDES_INPUT_FOR description: >- Angiotensin II is the agonist of both receptor branches; AGT hormone activity is causally upstream of AGTR1 (and AGTR2) receptor activity in gomodel:6246724f00000549. knowledge_gaps: - gap_statement: >- The molecular mechanism of AT2 (AGTR2) signalling remains incompletely defined and is sometimes contradictory: which G protein-dependent versus -independent routes activate SHP-1 versus MKP-1 in which cell types, how the non-canonical helix VIII conformation is reconciled with reported downstream effects, and whether MTUS1 and ZBTB16 act in the same or parallel AT2 branches, could only be resolved by new biochemical and structural experiments. gap_kind: - BIOLOGY - gap_statement: >- Whether the reported AT2 C-terminal-tail partners CNKSR1, ERBB3, SLC9A6 and TIMP3 transmit AT2 signals in vivo or only bind the receptor, and what distinct cellular outputs each confers, is unresolved and would require receptor-partner perturbation experiments; they are left out of this draft pending that evidence. gap_kind: - BIOLOGY