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

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.

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.