GPR161

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0001501 skeletal system development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse Gpr161, where conditional deletion in the limb bud causes derepressed Smoothened signalling and polysyndactyly, i.e. a skeletal patterning defect (mouse IMP, ECO:0000315, PMID:29222391 in the QuickGO record for UniProtKB:B2RPY5). Human GPR161 loss-of-function likewise produces skeletal and limb malformations. Reason: Skeletal system development is a whole developmental programme executed by chondrocytes, osteoblasts and the signalling networks that pattern the skeleton. GPR161's contribution is entirely upstream and indirect: it keeps the Hedgehog pathway off, and skeletal patterning goes wrong when it cannot. The transfer itself is sound: human GPR161 and mouse Gpr161 are direct orthologs in PANTHER subfamily PTHR22752:SF10, and the human and mouse receptors share both documented activities (constitutive Gs coupling and PKA anchoring). What is at issue is coreness, not correctness. GPR161 does not carry out a step of this developmental programme; it holds one signalling pathway off, and the tissue phenotype is what happens when that brake is released. Kept, marked non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is experimental (IMP, ECO:0000315), not itself a propagation; limb-conditional knockout gives polysyndactyly. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling file:human/GPR161/GPR161-uniprot.txt skeletal development, embryonic cerebellar development and forebrain file:human/GPR161/GPR161-notes.md are whole developmental programmes
GO:0004930 G protein-coupled receptor activity	IBA GO_REF:0000033	ACCEPT	Summary: PANTHER IBD node PTN002733799 in family PTHR22752 asserts G protein-coupled receptor activity for the GPR161/GPR101 clade, seeded by mouse Gpr161, mouse Gpr101 and human GPR161 itself (interpro/panther/PTHR22752/PTHR22752-paint.tsv). Human GPR161 inherits the assertion by descent. Reason: The node placement is correct and independently confirmed on the target: the 2.7 A cryo-EM structure of human GPR161 bound to heterotrimeric Gs captures the G-protein-coupled, active conformation, and miniGs recruitment plus cAMP accumulation assays show the receptor engages Gs in cells. Human GPR161's appearance in its own WITH/FROM list is expected, not circular: its experimental IDA row is one of the descendant evidences the PAINT curator used to place the IBD, and the IBA then adds the further claim that the activity is inherited rather than lineage-specific. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002733799 · PTN002733799 SUPPORTS TRANSFER IBD node for GO:0004930 in PTHR22752, seeded by MGI:2685054, MGI:2685858 and UniProtKB:Q8N6U8; human GPR161 sits inside the clade that inherited the activity and has its own IDA for the term. Supporting Evidence: PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor. PMID:38326651 The results from these two orthogonal assays demonstrate that GPR161 is constitutively active PMID:38326651 The orphan GPCR GPR161 has been characterized as a unique example of a constitutively active receptor that is located within the primary cilium of cells
GO:0004930 G protein-coupled receptor activity	IDA PMID:38326651 GPR161 structure uncovers the redundant role of sterol-regul...	ACCEPT	Summary: Hoppe et al. determined a 2.74 A cryo-EM structure of human GPR161 in complex with heterotrimeric Gs, and showed by GloSensor cAMP and miniGs NanoBiT complementation that the receptor couples to Gs constitutively; a cholesterol-like sterol at an extrahelical TM6/TM7 site stabilises the Gs-coupled conformation, and mutating that site ablates cAMP production and miniGs recruitment. Reason: This is the defining molecular function of the protein and is demonstrated directly in human cells and by structure. One nuance worth recording rather than acting on: GO:0004930's definition speaks of combining with an extracellular signal, whereas GPR161 has no agonist - its own ECL2 occupies the orthosteric pocket and a membrane-derived sterol acts as the activating stimulus. The operative half of the definition, transmitting a signal across the membrane by activating an associated G protein, is exactly what the structure and the miniGs assays establish, so the term is the right one and no modification is warranted. Supporting Evidence: PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor. PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production. PMID:38326651 The results from these two orthogonal assays demonstrate that GPR161 is constitutively active PMID:38326651 the ECL2 of GPR161 forms a beta hairpin that folds over the extracellular face of the receptor to completely occlude the canonical orthosteric ligand binding pocket
GO:0004930 G protein-coupled receptor activity	IEA GO_REF:0000002	ACCEPT	Summary: InterPro signature IPR000276 (G protein-coupled receptor, rhodopsin-like) maps to G protein-coupled receptor activity. GPR161 is a bona fide class A GPCR with a seven-transmembrane fold resolved by cryo-EM. Reason: The domain-to-term mapping lands on precisely the activity that the human IDA row and the PANTHER node independently support, so the electronic inference is correct for this protein rather than a generic family default. Supporting Evidence: PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor. file:human/GPR161/GPR161-uniprot.txt Belongs to the G protein-coupled receptor 1 family.
GO:0004930 G protein-coupled receptor activity	ISS GO_REF:0000024	ACCEPT	Summary: Curator transfer from mouse Gpr161 (UniProtKB:B2RPY5), whose own annotation for this term is experimental (IDA, ECO:0000314, PMID:23332756 in the QuickGO record for B2RPY5). Reason: A sound ortholog transfer that is in any case superseded by direct human evidence: the same term carries an IDA row on PMID:38326651 for human GPR161. Retained because duplicate rows with different evidence lines are informative about how the assertion was built, not a defect. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is IDA, not a propagation; human target additionally has its own IDA and cryo-EM structure for this activity. Supporting Evidence: PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor. PMID:38326651 The results from these two orthogonal assays demonstrate that GPR161 is constitutively active
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: A single interaction with UPK1B (uroplakin 1B, a urothelial plaque tetraspanin) detected in HuRI, the systematic human binary interactome map built from nine genome-scale yeast two-hybrid screens. No follow-up assay, no cellular context and no functional consequence is reported for this pair, in HuRI or elsewhere. Reason: Bare GO:0005515 carries no functional information: it records that two proteins can associate without saying what GPR161 does. The repository policy is to modify such a row when the cited paper supports a more informative molecular function, and otherwise to remove it. Here no more informative term is available - UPK1B is not part of any described GPR161 mechanism (the mechanistic partners are PRKAR1A/PRKAR1B, GNAS, ARRB1/ARRB2, TULP3 and SMO, none of which appears among these IntAct rows), and the HuRI authors state explicitly that function does not follow from detection. Removal is a judgement about the annotation's informativeness, not a claim that the reported interaction is false. GPR161's informative molecular functions are captured separately by GO:0004930 and GO:0035591, and a PKA-specific binding term is proposed as a NEW row. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: A single interaction with COMT (catechol O-methyltransferase, a cytosolic/membrane-anchored methyltransferase of catecholamine catabolism) detected in HuRI, the systematic human binary interactome map built from nine genome-scale yeast two-hybrid screens. No follow-up assay, no cellular context and no functional consequence is reported for this pair, in HuRI or elsewhere. Reason: Bare GO:0005515 carries no functional information: it records that two proteins can associate without saying what GPR161 does. The repository policy is to modify such a row when the cited paper supports a more informative molecular function, and otherwise to remove it. Here no more informative term is available - COMT is not part of any described GPR161 mechanism (the mechanistic partners are PRKAR1A/PRKAR1B, GNAS, ARRB1/ARRB2, TULP3 and SMO, none of which appears among these IntAct rows), and the HuRI authors state explicitly that function does not follow from detection. Removal is a judgement about the annotation's informativeness, not a claim that the reported interaction is false. GPR161's informative molecular functions are captured separately by GO:0004930 and GO:0035591, and a PKA-specific binding term is proposed as a NEW row. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: A single interaction with EFNA5 (ephrin-A5, a GPI-anchored EPH receptor ligand) detected in HuRI, the systematic human binary interactome map built from nine genome-scale yeast two-hybrid screens. No follow-up assay, no cellular context and no functional consequence is reported for this pair, in HuRI or elsewhere. Reason: Bare GO:0005515 carries no functional information: it records that two proteins can associate without saying what GPR161 does. The repository policy is to modify such a row when the cited paper supports a more informative molecular function, and otherwise to remove it. Here no more informative term is available - EFNA5 is not part of any described GPR161 mechanism (the mechanistic partners are PRKAR1A/PRKAR1B, GNAS, ARRB1/ARRB2, TULP3 and SMO, none of which appears among these IntAct rows), and the HuRI authors state explicitly that function does not follow from detection. Removal is a judgement about the annotation's informativeness, not a claim that the reported interaction is false. GPR161's informative molecular functions are captured separately by GO:0004930 and GO:0035591, and a PKA-specific binding term is proposed as a NEW row. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: A single interaction with CLDN19 (claudin-19, a tight-junction claudin) detected in HuRI, the systematic human binary interactome map built from nine genome-scale yeast two-hybrid screens. No follow-up assay, no cellular context and no functional consequence is reported for this pair, in HuRI or elsewhere. Reason: Bare GO:0005515 carries no functional information: it records that two proteins can associate without saying what GPR161 does. The repository policy is to modify such a row when the cited paper supports a more informative molecular function, and otherwise to remove it. Here no more informative term is available - CLDN19 is not part of any described GPR161 mechanism (the mechanistic partners are PRKAR1A/PRKAR1B, GNAS, ARRB1/ARRB2, TULP3 and SMO, none of which appears among these IntAct rows), and the HuRI authors state explicitly that function does not follow from detection. Removal is a judgement about the annotation's informativeness, not a claim that the reported interaction is false. GPR161's informative molecular functions are captured separately by GO:0004930 and GO:0035591, and a PKA-specific binding term is proposed as a NEW row. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: A single interaction with SLC30A2 (zinc transporter 2) detected in HuRI, the systematic human binary interactome map built from nine genome-scale yeast two-hybrid screens. No follow-up assay, no cellular context and no functional consequence is reported for this pair, in HuRI or elsewhere. Reason: Bare GO:0005515 carries no functional information: it records that two proteins can associate without saying what GPR161 does. The repository policy is to modify such a row when the cited paper supports a more informative molecular function, and otherwise to remove it. Here no more informative term is available - SLC30A2 is not part of any described GPR161 mechanism (the mechanistic partners are PRKAR1A/PRKAR1B, GNAS, ARRB1/ARRB2, TULP3 and SMO, none of which appears among these IntAct rows), and the HuRI authors state explicitly that function does not follow from detection. Removal is a judgement about the annotation's informativeness, not a claim that the reported interaction is false. GPR161's informative molecular functions are captured separately by GO:0004930 and GO:0035591, and a PKA-specific binding term is proposed as a NEW row. Supporting Evidence: PMID:32296183 We screened this search space a total of nine times with a panel of three Y2H assay versions PMID:32296183 the cellular function of most individual PPIs remains to be elucidated
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: Mapped from UniProt subcellular location SL-0039 (Cell membrane). UniProt records GPR161 as a multi-pass cell-membrane protein in addition to the cilium membrane, and the structure paper argues that the plasma-membrane pool, where accessible sterol is more abundant than in the ciliary membrane, can itself support cAMP production. Reason: Correct and functionally relevant, not merely a default for a seven-transmembrane protein. The non-ciliary pools of GPR161 are an active part of the mechanism: both ciliary and extraciliary receptor contribute to GLI repressor formation in mouse. The more specific GO:0098804 non-motile cilium membrane, a descendant of this term, is annotated separately with direct evidence; keeping the parent records the extraciliary pool. Supporting Evidence: PMID:38326651 Therefore, both the plasma membrane and periciliary endosomal pools could support cAMP production by GPR161. PMID:38326651 Both ciliary and extraciliary pools of GPR161 contribute to GLI-R formation and regulate tissue-specific repression of Hedgehog pathway in mice file:human/GPR161/GPR161-uniprot.txt Cell membrane {ECO:0000269\|PubMed:20889716, ECO:0000269\|PubMed:40384633}
GO:0007186 G protein-coupled receptor signaling pathway	IEA GO_REF:0000002	MODIFY	Summary: InterPro IPR000276 maps the generic rhodopsin-like GPCR signature to G protein-coupled receptor signaling pathway. For GPR161 the specific transduction route is established: it couples to G(s)/GNAS and activates adenylate cyclase, which the direct child term GO:0007189 names. Reason: Directionally right but uninformatively broad for a receptor whose coupling has been resolved structurally and pharmacologically. GO:0007189, the adenylate cyclase-activating branch, is already supported here by IDA, IBA, ISS and an ARBA rule; stating only that GPR161 signals through some G protein adds nothing beyond its molecular-function annotation. Replaced by the specific child. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production. PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: PANTHER IBD node PTN004562730, restricted to taxon:7711 (Chordata), asserts the adenylate cyclase-activating GPCR pathway for the GPR161 clade, seeded by mouse Gpr161, human GPR161 and zebrafish gpr161 (interpro/panther/PTHR22752/PTHR22752-paint.tsv). Reason: The node is the GPR161-specific one and its Chordata scope matches the distribution of the ciliary cAMP brake; the three seeds span mouse, human and fish, each with experimental support. Cholesterol-dependent Gs coupling driving cAMP production is demonstrated directly for the human protein, so the target sits squarely inside the clade that inherited the function. As with GO:0004930, human GPR161 appearing among the node's seeds reflects its own experimental grounding and is not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004562730 · PTN004562730 SUPPORTS TRANSFER Chordata-scoped IBD node for GO:0007189 seeded by MGI:2685054, UniProtKB:Q8N6U8 and ZFIN:ZDB-GENE-120215-39; the target is inside the clade and carries its own IDA. Supporting Evidence: PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production. PMID:38326651 The results from these two orthogonal assays demonstrate that GPR161 is constitutively active
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IDA PMID:38326651 GPR161 structure uncovers the redundant role of sterol-regul...	ACCEPT	Summary: In HEK293 cells, wild-type GPR161 raises basal cAMP far above empty vector and recruits miniGs; disrupting the extrahelical sterol site (I323A/W327A/R332A) ablates both cAMP production and miniGs recruitment, tying the cAMP output directly to GPR161-Gs coupling. Reason: Direct assay of the pathway output in human cells with the human protein, with a structure-guided loss-of-function control. This is a core process for GPR161: it is the receptor itself that performs the G-protein activation step that leads to adenylate cyclase activation. Supporting Evidence: PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production. PMID:38326651 The results from these two orthogonal assays demonstrate that GPR161 is constitutively active PMID:38326651 We conclude that our structure of GPR161-miniGs captures the Gs coupled, active conformation of the receptor.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: ARBA rule ARBA00029026 assigns the adenylate cyclase-activating GPCR pathway from GPR161's UniProt family and functional annotation. Reason: The machine-learned assignment lands on exactly the term that the human IDA row and the Chordata-scoped PAINT node independently support, so it is correct for this protein rather than a broad family default. Supporting Evidence: file:human/GPR161/GPR161-uniprot.txt G(s)/GNAS, mediating activation of adenylate cyclase activity and PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production.
GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Curator transfer from mouse Gpr161 (UniProtKB:B2RPY5), whose annotation for this term is experimental (IDA, ECO:0000314, PMID:23332756 in the QuickGO record for B2RPY5). Reason: Sound ortholog transfer, and in this case superseded by the human IDA row on the same term. The mouse and human receptors use the same Gs/adenylate cyclase route, so there is no divergence to argue about. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is IDA, not a propagation; human target has its own IDA for the same term. Supporting Evidence: PMID:38326651 Our combined biochemical, simulation, and signaling studies show that cholesterol, and potentially other sterols, can bind GPR161 to support interactions with Gs, thereby promoting cAMP production. PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling
GO:0016020 membrane	IEA GO_REF:0000002	MODIFY	Summary: InterPro signatures IPR000276 and IPR017452 place GPR161 in a membrane. The specific membranes in which the receptor sits and acts are established: the non-motile cilium membrane and the plasma membrane. Reason: Correct but too coarse to say anything about GPR161. The receptor's compartment is the crux of its biology - it works in the primary cilium and is removed from it when the pathway turns on - so the bare membrane term should be replaced by the two specific membranes for which there is direct evidence. Proposed replacements: non-motile cilium membrane plasma membrane Supporting Evidence: PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition PMID:38326651 Therefore, both the plasma membrane and periciliary endosomal pools could support cAMP production by GPR161.
GO:0021549 cerebellum development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse Gpr161, where conditional deletion in neural stem cells or in cerebellar granule-cell progenitors derepresses Smoothened signalling and induces cerebellar tumorigenesis (mouse IMP, ECO:0000315, PMID:29386106 in the QuickGO record for UniProtKB:B2RPY5). Germline GPR161 variants predispose to human medulloblastoma, a cerebellar tumour. Reason: Cerebellar development is carried out by granule-cell progenitors, Purkinje cells and the SHH signal that drives their proliferation. GPR161 does not execute a step of that programme; it sets how much Hedgehog output the progenitors see. The transfer itself is sound: human GPR161 and mouse Gpr161 are direct orthologs in PANTHER subfamily PTHR22752:SF10, and the human and mouse receptors share both documented activities (constitutive Gs coupling and PKA anchoring). What is at issue is coreness, not correctness. GPR161 does not carry out a step of this developmental programme; it holds one signalling pathway off, and the tissue phenotype is what happens when that brake is released. Kept, marked non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is experimental (IMP); conditional deletion in cerebellar granule-cell progenitors causes tumorigenesis. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling file:human/GPR161/GPR161-uniprot.txt skeletal development, embryonic cerebellar development and forebrain
GO:0030666 endocytic vesicle membrane	TAS Reactome:R-HSA-5635102	KEEP AS NON CORE	Summary: Reactome reaction R-HSA-5635102 'GPR161 is internalized' places the receptor in the endocytic vesicle membrane as it leaves the cilium on Hedgehog pathway activation. The internalisation itself is well documented: GRK2 phosphorylation recruits beta-arrestin, and the BBSome with IFT-B exports the receptor, which then reaches the recycling endocytic compartment. Reason: A genuine but transient transit compartment. No activity of GPR161 has been assayed in the endocytic vesicle, in contrast to the recycling endosome, where the extraciliary receptor pool is reported to contribute to GLI repressor formation. Kept as a correct localisation and marked non-core; the functionally meaningful post-ciliary compartment is GO:0055037. Supporting Evidence: PMID:38326651 Upon Hedgehog pathway activation, GPR161 exits cilia by internalizing to the recycling endocytic compartment PMID:40384633 and ARRB2 double-knockout impairs GPR161 export. Reactome:R-HSA-5635102 Hh signaling promotes the removal of the orphan G protein coupled receptor GPR161 from the cilium
GO:0030900 forebrain development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse Gpr161, where conditional deletion in neuroepithelial cells and radial glia at early mid-gestation derepresses Smoothened signalling throughout the forebrain, producing hydrocephalus, periventricular heterotopia and polymicrogyria (mouse IMP, ECO:0000315, PMID:30914320 in the QuickGO record for UniProtKB:B2RPY5). Reason: Forebrain development is an organ-level programme; GPR161 contributes by holding Hedgehog output down in neural progenitors, and the malformations are the consequence of losing that restraint. The transfer itself is sound: human GPR161 and mouse Gpr161 are direct orthologs in PANTHER subfamily PTHR22752:SF10, and the human and mouse receptors share both documented activities (constitutive Gs coupling and PKA anchoring). What is at issue is coreness, not correctness. GPR161 does not carry out a step of this developmental programme; it holds one signalling pathway off, and the tissue phenotype is what happens when that brake is released. Kept, marked non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is experimental (IMP) from a conditional forebrain knockout. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling file:human/GPR161/GPR161-uniprot.txt skeletal development, embryonic cerebellar development and forebrain
GO:0035591 signaling adaptor activity	IDA PMID:38326651 GPR161 structure uncovers the redundant role of sterol-regul...	ACCEPT	Summary: GPR161 is the only GPCR known to carry an A-kinase anchoring domain: an amphipathic helix in its cytoplasmic tail binds type I PKA regulatory subunits directly. Hoppe et al. showed that the helix-breaking L465P substitution reduces PKA-RI recruitment while leaving Gs coupling and cAMP production intact, and that this mutant - unlike the cAMP-dead sterol-site mutant - fails to keep GLI2 out of the ciliary tip. Anchoring PKA, not making cAMP, is what the ciliary brake requires. Reason: An exact fit to the term. GO:0035591 is defined as bringing protein and non-protein molecules together within a signalling pathway by tethering components and localising them to a specific part of the cell, which is what the AKAP helix does: it holds the PKA type I holoenzyme at the ciliary membrane where it phosphorylates GLI2 and GLI3. The mutant pair dissociates this activity from GO:0004930 cleanly, so the two molecular functions on this gene product are complementary rather than redundant, and the curated GO-CAMs (693b3c0900000157, 693b3c0900000331, 693b3c0900000434) model GPR161 with exactly these two activity nodes. Supporting Evidence: PMID:38326651 GPR161 is unique among many GPCRs in that it contains a PKA-binding AKAP domain. PMID:38326651 Previous studies have identified an amphipathic helix in the C-terminus of GPR161 that directly binds PKA regulatory subunits type I (RI) PMID:38326651 Consistent with previous reports, GPR161-L465PC-term recruited less PKA-RI than wild-type GPR161 PMID:38326651 was unable to repress GLI2 localization to the ciliary tip in the basal condition, indicating that PKA anchoring by GPR161 is critical for ciliary Hedgehog pathway control PMID:38326651 We conclude that GPR161 binding to PKA-RI is essential for Hedgehog repression in the primary cilia, while GPR161-induced Gs signaling is dispensable.
GO:0035591 signaling adaptor activity	IEA GO_REF:0000117	ACCEPT	Summary: ARBA rule ARBA00090724 assigns signaling adaptor activity from GPR161's UniProt annotation, which records the AKAP region and direct association with PRKAR1A and PRKAR1B. Reason: The rule reproduces the term that the human IDA row establishes experimentally, so the electronic assignment is right for this protein. It is also unusually specific for an ARBA rule, which reflects the fact that the AKAP feature is annotated on the UniProt entry rather than inferred from family membership. Supporting Evidence: file:human/GPR161/GPR161-uniprot.txt GPR161 also activates PKA by acting as a PKA-anchoring protein, which PMID:38326651 GPR161 is unique among many GPCRs in that it contains a PKA-binding AKAP domain.
GO:0035591 signaling adaptor activity	ISS GO_REF:0000024	ACCEPT	Summary: Curator transfer from mouse Gpr161 (MGI:2685054), whose annotation for this term is experimental (IDA, ECO:0000314, PMID:27357676 in the QuickGO record for UniProtKB:B2RPY5) - the study that identified the GPR161 AKAP helix and its direct binding to PRKAR1A and PRKAR1B. Reason: Sound transfer from the experiment that established the activity, and confirmed on the human protein by the IDA row on PMID:38326651. The AKAP helix is present in the human C-terminal tail (the L465P substitution that breaks it was made in human GPR161), so there is no question of the feature being mouse-specific. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2685054 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is IDA from the study that mapped the AKAP helix; the human target has its own IDA on the same term. Supporting Evidence: PMID:38326651 Previous studies have identified an amphipathic helix in the C-terminus of GPR161 that directly binds PKA regulatory subunits type I (RI) PMID:38326651 Consistent with previous reports, GPR161-L465PC-term recruited less PKA-RI than wild-type GPR161
GO:0045879 negative regulation of smoothened signaling pathway	IDA PMID:38326651 GPR161 structure uncovers the redundant role of sterol-regul...	ACCEPT	Summary: In Gpr161-null NIH 3T3 cells, GLI2 accumulates at the ciliary tip in the basal state and re-expression of wild-type GPR161 restores repression. The AKAP-defective L465P mutant localises to cilia normally but cannot repress ciliary GLI2, whereas the cAMP-dead sterol-site mutant can, identifying PKA anchoring as the arm of GPR161 that holds the pathway off. Reason: The core biological process for this gene. GPR161 itself performs the steps that suppress the pathway: it activates Gs to raise cAMP and it tethers PKA at the ciliary membrane, where the kinase converts GLI2 and GLI3 into repressors. The rescue design with structure-guided separation-of-function mutants makes this a direct assay of the process rather than an inference from a phenotype. Supporting Evidence: PMID:38326651 was unable to repress GLI2 localization to the ciliary tip in the basal condition, indicating that PKA anchoring by GPR161 is critical for ciliary Hedgehog pathway control PMID:38326651 We conclude that GPR161 binding to PKA-RI is essential for Hedgehog repression in the primary cilia, while GPR161-induced Gs signaling is dispensable. PMID:38326651 In the absence of Hedgehog, GPR161 bound to PKA is localized to primary cilia. PKA within the cilia phosphorylates GLI resulting in processing into its repressor form.
GO:0045879 negative regulation of smoothened signaling pathway	IEA GO_REF:0000117	ACCEPT	Summary: ARBA rule ARBA00086554 assigns negative regulation of the smoothened signaling pathway from GPR161's UniProt functional annotation, which describes it as a key inhibitor of the pathway in primary cilia. Reason: The rule reproduces the term that the human IDA row and the mouse ortholog transfer both support, and that every curated GO-CAM containing GPR161 uses for its adaptor activity. Correct for this protein. Supporting Evidence: file:human/GPR161/GPR161-uniprot.txt G protein-coupled receptor that acts as a key inhibitor of PMID:38326651 We conclude that GPR161 binding to PKA-RI is essential for Hedgehog repression in the primary cilia, while GPR161-induced Gs signaling is dispensable.
GO:0045879 negative regulation of smoothened signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: Curator transfer from mouse Gpr161 (MGI:2685054), whose annotations for this term are experimental - IDA on PMID:27357676 and PMID:38326651, plus four independent IMP rows from conditional-knockout studies (QuickGO record for UniProtKB:B2RPY5). Reason: One of the best-supported transfers in this record: the mouse source has direct and genetic evidence from several laboratories, and the human protein carries its own IDA for the same term. Mouse and human GPR161 use the same two mechanisms to hold the pathway off, so no divergence argument is available. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2685054 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source rows are IDA and IMP from several studies, not propagations; the human target also has its own IDA. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling PMID:38326651 We conclude that GPR161 binding to PKA-RI is essential for Hedgehog repression in the primary cilia, while GPR161-induced Gs signaling is dispensable.
GO:0055037 recycling endosome	IBA GO_REF:0000033	ACCEPT	Summary: PANTHER IBD node PTN004562730, scoped to taxon:7711 (Chordata), places GPR161 in the recycling endosome, seeded by mouse Gpr161. On Hedgehog pathway activation the receptor exits the cilium into the recycling endocytic compartment, and the extraciliary pool is reported to contribute to GLI repressor formation. Reason: Accepted including the is_active_in qualifier. Internalisation of GPR161 into recycling endosomes is directly documented, and there is a functional case for activity there rather than mere residence: ciliary and extraciliary pools both contribute to GLI repressor formation in mouse, sterols are enriched in the recycling compartment, and the receptor's Gs coupling is sterol-dependent. That the node has a single seed does not weaken it - an IBD asserts where in the tree a property arose, and the Chordata restriction is the right scope for a GPR161-clade trafficking behaviour. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004562730 · PTN004562730 SUPPORTS TRANSFER Chordata-scoped IBD node for GO:0055037, seeded by MGI:2685054 alone; a single-donor node is a phylogenetic placement judgement, not weak similarity evidence, and the human receptor is inside the clade. Supporting Evidence: PMID:38326651 Upon Hedgehog pathway activation, GPR161 exits cilia by internalizing to the recycling endocytic compartment PMID:38326651 Both ciliary and extraciliary pools of GPR161 contribute to GLI-R formation and regulate tissue-specific repression of Hedgehog pathway in mice PMID:38326651 Sterols are also enriched in the endocytic recycling compartment PMID:38326651 Therefore, both the plasma membrane and periciliary endosomal pools could support cAMP production by GPR161.
GO:0055037 recycling endosome	ISS GO_REF:0000024	ACCEPT	Summary: Curator transfer from mouse Gpr161 (UniProtKB:B2RPY5), whose annotation for this term is experimental (IDA, ECO:0000314, PMID:23332756 in the QuickGO record for B2RPY5) - the study that first showed Hedgehog-induced GPR161 exit from cilia into recycling endosomes. Reason: Sound transfer from the imaging study that established the compartment, and consistent with the human data: the structure paper describes GPR161 internalising to the recycling endocytic compartment on pathway activation and argues that this pool can support cAMP production. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is IDA from live-cell imaging of Hedgehog-induced GPR161 internalisation. Supporting Evidence: PMID:38326651 Upon Hedgehog pathway activation, GPR161 exits cilia by internalizing to the recycling endocytic compartment PMID:38326651 Therefore, both the plasma membrane and periciliary endosomal pools could support cAMP production by GPR161.
GO:0060170 ciliary membrane	IEA GO_REF:0000044	ACCEPT	Summary: Mapped from UniProt subcellular location SL-0305 (Cilium membrane). GPR161 is a resident of the primary cilium membrane, recruited there by TULP3 and the IFT-A complex and removed on Hedgehog pathway activation. Reason: Correct and central to the protein's function. The more specific descendant GO:0098804 non-motile cilium membrane is annotated separately with direct evidence; the SubCell-derived parent cannot distinguish motile from non-motile cilia, so it is accepted at the granularity its source supports rather than rewritten. Supporting Evidence: PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition PMID:40384633 Specific G-protein-coupled receptors (GPCRs) exist on the ciliary membrane. PMID:38326651 The orphan GPCR GPR161 has been characterized as a unique example of a constitutively active receptor that is located within the primary cilium of cells
GO:0060170 ciliary membrane	TAS Reactome:R-HSA-5610725	ACCEPT	Summary: Reactome reaction R-HSA-5610725 'TULP3 is required for GPR161 localization in the cilium' asserts the ciliary membrane location and its dependence on TULP3 and the IFT-A complex, consistent with the original demonstration that TULP3/IFT-A traffic a subset of GPCRs, but not Smoothened, into cilia. Reason: Correct location, correctly attributed. Reactome's author statement matches the primary literature and the human IDA row for the more specific non-motile cilium membrane term. Supporting Evidence: PMID:20889716 trafficking of a subset of G protein-coupled receptors (GPCRs), but not Reactome:R-HSA-5610725 TULP3 and the retrograde complex IFT-A are required to recruit GPR161 to the cilium in the absence of Hh ligand PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition
GO:0060170 ciliary membrane	TAS Reactome:R-HSA-5635102	ACCEPT	Summary: Reactome reaction R-HSA-5635102 'GPR161 is internalized' assigns the ciliary membrane as the compartment the receptor leaves when Hedgehog signalling begins. Reason: Correct. The ciliary membrane is where GPR161 resides in the pathway-off state, and its Hedgehog-induced removal from that membrane is part of pathway activation, confirmed in human cells. Supporting Evidence: PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition PMID:38326651 In the presence of Hedgehog, GPR161 traffics out of the cilia, removing PKA-RI with it PMID:40384633 demonstrated that GRK2 plays a crucial role in GPR161 export.
GO:0060173 limb development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse Gpr161, where limb-conditional deletion increases Smoothened signalling and produces polysyndactyly (mouse IMP, ECO:0000315, PMID:29222391 in the QuickGO record for UniProtKB:B2RPY5); the null embryos show severe limb defects. Reason: Limb development is a programme executed by limb-bud mesenchyme and its signalling centres. GPR161 modulates one input to it. The transfer itself is sound: human GPR161 and mouse Gpr161 are direct orthologs in PANTHER subfamily PTHR22752:SF10, and the human and mouse receptors share both documented activities (constitutive Gs coupling and PKA anchoring). What is at issue is coreness, not correctness. GPR161 does not carry out a step of this developmental programme; it holds one signalling pathway off, and the tissue phenotype is what happens when that brake is released. Kept, marked non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is experimental (IMP) from a limb-conditional knockout with a polysyndactyly phenotype. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling file:human/GPR161/GPR161-uniprot.txt pathway during early neural tube development, forelimb formation,
GO:0098804 non-motile cilium membrane	IDA PMID:40384633 β-Arrestin mediates the export of ciliary GPR161 but not Smo...	ACCEPT	Summary: Fujii et al. imaged GPR161 in the primary cilium membrane and dissected its export: GRK2 phosphorylates the receptor, beta-arrestin 1/2 bind it, and the BBSome with IFT-B carry it out; ARRB1/ARRB2 double knockout blocks export and GPR161 accumulates in cilia when IFT27 or the BBSome is missing. UniProt cites this study for the cilium membrane location with experimental evidence. Reason: This is the core location, and is_active_in is the right qualifier: GPR161's receptor activity and its PKA anchoring both operate in the ciliary membrane, and the pathway-off state depends on the receptor being there. Our cache holds only the abstract of this paper, so the quoted support is abstract-level; the curator who made the annotation read the full text, and the same location is independently established for human GPR161 in PMID:38326651. Note also that GPR161 is the cargo of the export machinery described here, not one of its actors - in GO-CAM 693b3c0900000716 the intraciliary retrograde transport activities belong to GRK2, ARRB1, the BBSome and IFT-B - so no transport process term is warranted for GPR161. Supporting Evidence: PMID:40384633 Specific G-protein-coupled receptors (GPCRs) exist on the ciliary membrane. PMID:40384633 and ARRB2 double-knockout impairs GPR161 export. PMID:40384633 demonstrated that GRK2 plays a crucial role in GPR161 export. PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition file:human/GPR161/GPR161-uniprot.txt Cell projection, cilium membrane
GO:0098804 non-motile cilium membrane	IEA GO_REF:0000117	ACCEPT	Summary: ARBA rule ARBA00091729 assigns the non-motile cilium membrane from GPR161's UniProt subcellular location annotation. Reason: The electronic assignment lands on the most specific correct compartment, matching the human IDA row and the location used for the GPR161 activity node in every curated GO-CAM that contains it. Supporting Evidence: PMID:38326651 GPR161 localizes to primary cilia in Hedgehog pathway responsive NIH 3T3 cells in the basal condition PMID:38326651 The orphan GPCR GPR161 has been characterized as a unique example of a constitutively active receptor that is located within the primary cilium of cells
GO:1901621 negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning	ISS GO_REF:0000024	ACCEPT	Summary: Transferred from mouse Gpr161, where the null embryo dies by 10.5 dpc with increased Shh signalling, ventralisation throughout the developing neural tube and defective Gli3 processing (mouse IMP, ECO:0000315, PMID:23332756 in the QuickGO record for UniProtKB:B2RPY5). Human GPR161 variants are found in spina bifida, a neural tube closure defect. Reason: Accepted as core, in contrast to the tissue-level developmental terms on this record. This term is a descendant of GO:0045879 and names the regulatory act GPR161 itself performs - holding Smoothened signalling down - in the tissue where that act is essential, rather than naming a developmental programme that GPR161 merely modulates. The dorsoventral neural tube is where the graded Hedgehog readout that GPR161 sets is the actual patterning mechanism, and the mouse phenotype is the direct readout of losing it. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is experimental (IMP): the null embryo ventralises throughout the neural tube and fails to process Gli3. Supporting Evidence: PMID:38326651 Knockout of Gpr161 in mice is embryonically lethal, and the embryos display severe limb, facial, and early nervous system defects indicative of hyperactive Hedgehog signaling PMID:38326651 In the absence of Hedgehog, GPR161 bound to PKA is localized to primary cilia. PKA within the cilia phosphorylates GLI resulting in processing into its repressor form. PMID:38326651 We conclude that GPR161 binding to PKA-RI is essential for Hedgehog repression in the primary cilia, while GPR161-induced Gs signaling is dispensable.
GO:2001222 regulation of neuron migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Transferred from mouse Gpr161, where the receptor was shown to act as a mechanosensor of fluid shear stress that drives the saltatory migration of neurons during brain development (mouse IDA, ECO:0000314, PMID:40737401 in the QuickGO record for UniProtKB:B2RPY5). Reason: Correct and interesting: this is an emerging second context for GPR161, distinct from Hedgehog repression, in which the receptor is proposed to read mechanical rather than chemical input. But neuron migration is performed by the migrating neuron; GPR161 modulates it by setting a second-messenger level. Kept and marked non-core pending human-level evidence, of which there is none yet - the human annotation rests entirely on this single mouse study. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:B2RPY5 · Gpr161 (mouse) SUPPORTS TRANSFER Mouse source row is IDA; single study, no independent human evidence yet. Supporting Evidence: file:human/GPR161/GPR161-uniprot.txt Involved in the saltatory migration of neurons during brain development file:human/GPR161/GPR161-uniprot.txt as a constitutively active receptor or as a mechanosensitive receptor
GO:0034237 protein kinase A regulatory subunit binding	IPI PMID:38326651 GPR161 structure uncovers the redundant role of sterol-regul...	NEW	Summary: GPR161 binds type I PKA regulatory subunits directly through an amphipathic helix in its cytoplasmic tail, a feature it does not share with any other GPCR. Hoppe et al. measured PKA-RI recruitment by human GPR161 in human cells and showed that the helix-breaking L465P substitution reduces it while leaving Gs coupling untouched, and that the same substitution abolishes repression of ciliary GLI2. Reason: GOA has the downstream consequence of this binding (GO:0035591 signaling adaptor activity) but not the binding itself, which is the specific, assayable molecular interaction the AKAP region performs. GO:0034237 is defined as binding to one or both regulatory subunits of protein kinase A, which is exactly what is measured. It is not redundant with GO:0035591: that term sits under GO:0060090 molecular adaptor activity and describes the tethering role, whereas GO:0034237 sits under GO:0005515 and names the partner, so neither is an ancestor of the other. It is proposed conservatively, as the informative binding term that the five generic GO:0005515 rows on this record fail to supply, and is the only NEW row here - no process term is proposed, because every Hedgehog-pathway process GPR161 participates in is already annotated and the transport and GLI-processing steps around it are performed by other gene products. Supporting Evidence: PMID:38326651 GPR161 is unique among many GPCRs in that it contains a PKA-binding AKAP domain. PMID:38326651 Previous studies have identified an amphipathic helix in the C-terminus of GPR161 that directly binds PKA regulatory subunits type I (RI) PMID:38326651 Consistent with previous reports, GPR161-L465PC-term recruited less PKA-RI than wild-type GPR161 PMID:38326651 was unable to repress GLI2 localization to the ciliary tip in the basal condition, indicating that PKA anchoring by GPR161 is critical for ciliary Hedgehog pathway control

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