Gprc5c (retinoic acid-induced gene 3, RAIG-3) encodes an orphan class C (family 3) seven-transmembrane G protein-coupled receptor of the chordate-specific GPRC5 group. Unlike other class C receptors it has only a short extracellular N-terminus and no Venus flytrap ligand-binding domain. It is induced by all-trans retinoic acid and is expressed mainly in peripheral tissues, including kidney proximal tubule (apical membrane), pancreatic islets, vascular smooth muscle, olfactory sensory neurons and dormant haematopoietic stem cells. In bone marrow, hyaluronic acid (and its N-acetylglucosamine subunit) signals through GPRC5C to raise intracellular calcium and keep haematopoietic stem cells dormant; Gprc5c-deficient stem cells divide faster and lose self-renewal under stress. In smooth muscle, GPRC5C dimerizes with the angiotensin II receptor AT1 (and with prostanoid receptors EP2 and IP) and facilitates angiotensin II binding and AT1-dependent contraction. In olfactory sensory neurons it sits at the ciliary transition zone and shapes ciliary composition. Additional roles in renal acid-base handling (via NHE3), beta-cell insulin secretion, osteoblast differentiation and leukemia stem cell metabolism have been reported. No endogenous ligand has been confirmed by direct binding, and there is no evidence that it binds the receptor tyrosine kinase ROS1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO from the GPCR family 3 7TM domain (IPR017978). Gprc5c is a class C 7TM receptor; hyaluronic acid/NAG and saccharides evoke Gq-type calcium signals in GPRC5C-expressing cells, and knockdown lowers islet cAMP. Reason: The family assignment is sound (UniProt places it in the GPCR 3 family) and functional data show that GPRC5C transduces extracellular cues (hyaluronic acid in HSCs, alkaline pH in kidney, saccharides in heterologous cells) into intracellular second-messenger signals. The receptor is orphan, so no ligand-specific child term is warranted. This is the core molecular function. Supporting Evidence: file:mouse/Gprc5c/Gprc5c-uniprot.txt Belongs to the G protein-coupled receptor 3 family. PMID:35725769 Addition of HA and NAG induced an increase in intracellular calcium levels, indicating that both activate GPRC5C signalling PMID:10945465 places them within the type 3 GPCR family |
| GO:0005118 sevenless binding | IEA GO_REF:0000002 | REMOVE | Summary: InterPro2GO from IPR002956 "Bride of sevenless protein", a family defined by a single PRINTS fingerprint (PR01223). Among Swiss-Prot entries it matches only the two Drosophila BOSS proteins and mouse Gprc5c; human GPRC5C and all other GPRC5 members do not match. On Gprc5c the hits are two fingerprint segments (residues 48-73 and 241-265) that lie on TM1 and TM6, i.e. generic 7TM sequence. This is the annotation flagged by Wei et al. 2020 (PMID:32470107). Reason: Sevenless binding by BOSS is made by its large extracellular region (a C-terminal peptide of the BOSS ECR contacts the third FNIII domain of Sevenless/dROS1). Gprc5c has a 27-residue extracellular N-terminus and lacks any such domain; the GPRC5 group is chordate-specific and only distantly related to insect BOSS, whose ECR is not conserved even outside Diptera. Vertebrates do have the Sevenless ortholog ROS1, so taxon alone is not the objection, but no study links any GPRC5 receptor to ROS1 (PubMed search 2026-10-19), and the physiological mammalian ROS1 ligand is the secreted EGF-like protein NELL2. The annotation rests on a species-idiosyncratic PRINTS hit in transmembrane segments that the human ortholog does not share, so the InterPro2GO transfer is a false positive. The Wei et al. flag holds, for a mapping reason rather than a taxon reason. Supporting Evidence: file:mouse/Gprc5c/Gprc5c-bioinformatics/RESULTS.md Q9NQ84 human GPRC5C: IPR002956 match = no file:mouse/Gprc5c/Gprc5c-bioinformatics/RESULTS.md residues 241-265 (score 32) PMID:39827240 This includes beta-strands in dROS1's third Fibronectin type III (FNIII) domain and a C-terminal peptide in BOSS' ECR. PMID:21827690 The invertebrate receptors have long N-termini, like other class C GPCRs and unlike GPRC5 receptors in Chordata PMID:18392882 The extracellular region, however, is only detectably conserved within but not outside Diptera. PMID:32499443 neural epidermal growth factor-like-like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1) |
| GO:0005739 mitochondrion | HDA PMID:14651853 Integrated analysis of protein composition, tissue diversity... | MARK AS OVER ANNOTATED | Summary: High-throughput mitochondrial proteome of mouse brain, heart, kidney and liver (Mootha et al. 2003). Only the abstract is cached; Gprc5c is not discussed. Reason: Gprc5c is a signal-peptide-bearing multi-pass plasma membrane receptor, found at the apical membrane of kidney proximal tubule (a tissue in this proteome) and at the olfactory ciliary transition zone. Nothing in its biology suggests a mitochondrial location, and kidney membrane preparations commonly carry plasma-membrane contaminants. Not removed because the dataset itself was not re-examined, but it should not be read as a functional location. Supporting Evidence: PMID:14651853 we performed a proteomic survey of mitochondria from mouse brain, heart, kidney, and liver PMID:29196502 Gprc5c localized to the apical membrane of renal proximal tubules (PTs) in mice, rats, and humans. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GPRC5 family node; GPRC5C is a cell-surface receptor. Reason: Cell-surface expression of tagged RAIG-3 and apical-membrane localization in kidney proximal tubule support the plasma membrane as the site of action. Supporting Evidence: PMID:10945465 demonstrated RAIG-2 and RAIG-3 expression at the cell surface PMID:29196502 Gprc5c localized to the apical membrane of renal proximal tubules (PTs) in mice, rats, and humans. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location "Cell membrane; Multi-pass membrane protein". Reason: Consistent with the experimental cell-surface and apical-membrane data. Supporting Evidence: PMID:10945465 demonstrated RAIG-2 and RAIG-3 expression at the cell surface |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Transferred from human GPRC5C, which has direct plasma membrane evidence. Reason: Consistent with mouse kidney apical-membrane localization. Supporting Evidence: PMID:29196502 Gprc5c localized to the apical membrane of renal proximal tubules (PTs) in mice, rats, and humans. |
| GO:0005929 cilium | ISO GO_REF:0000119 | MODIFY | Summary: Transferred from human GPRC5C. Mouse data (Bhat et al. 2023) place GPRC5C at the base of olfactory sensory cilia, specifically the ciliary transition zone, and not in primary cilia. Reason: The location is correct but more specific evidence exists: GPRC5C is at the ciliary transition zone, a term this gene already carries (GO:0035869). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q9NQ84 · GPRC5C SOURCE STALE OR MISSING Human GPRC5C no longer carries a cilium annotation in QuickGO (checked 2026-10-19); mouse imaging supports the narrower transition-zone location. Proposed replacements: ciliary transition zone Supporting Evidence: PMID:38110903 GPRC5C is located at the base of sensory cilia in olfactory neurons, but not in primary cilia of immature neurons or stem cells PMID:38110903 In closer examination, GPRC5C was found in the ciliary transition zone. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO from the GPCR family 3 7TM domain. Reason: GPRC5C signals as a GPCR: HA/NAG raise intracellular calcium through GPRC5C, and the receptor also modulates AT1 signalling. The process term is appropriate for an orphan receptor. Supporting Evidence: PMID:35725769 Addition of HA and NAG induced an increase in intracellular calcium levels, indicating that both activate GPRC5C signalling PMID:28228611 Down-regulation of Gprc5c led to both moderately reduced glucose-stimulated insulin release and also reduced cAMP content in mouse islets. |
| GO:0007601 visual perception | IEA GO_REF:0000002 | REMOVE | Summary: Second InterPro2GO mapping from the Bride-of-sevenless family (IPR002956), which reflects the role of BOSS in R7 photoreceptor induction in the Drosophila eye. Reason: Same false-positive family hit as the sevenless binding row: the PRINTS match is on TM1/TM6 only, the human ortholog does not match, and GPRC5 receptors are a chordate-specific group unrelated to the BOSS ectodomain function. No study reports a role for Gprc5c in the eye or in vision; Gprc5c-deficient mice are viable without overt CNS or behavioral phenotypes. Supporting Evidence: file:mouse/Gprc5c/Gprc5c-bioinformatics/RESULTS.md Q9NQ84 human GPRC5C: IPR002956 match = no PMID:21827690 Together our results suggest that GPRC5 receptors seem to be a chordate specific class of GPCRs. PMID:21840300 GPRC5C-deficient mice have no apparent behavioral deficits |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Combined IEA (ARBA, IPR017978 and the false-positive IPR002956). True but general. Reason: Gprc5c is a multi-pass plasma membrane receptor; the specific supported term is plasma membrane, which the gene already carries (IBA, IEA and ISO). Proposed replacements: plasma membrane Supporting Evidence: PMID:10945465 demonstrated RAIG-2 and RAIG-3 expression at the cell surface |
| GO:0030295 protein kinase activator activity | IBA GO_REF:0000033 | UNDECIDED | Summary: IBA at the GPRC5 node seeded by human GPRC5B (Q9NZH0), which has an IDA for this term (GPRC5B activation of Fyn kinase). Reason: Gprc5c sits inside the clade, so the node placement is not obviously wrong, but no study tests direct kinase activation by GPRC5C. Reported downstream effects (increased ERK1/2 activity on overexpression, NF-kB activation in AML) are indirect signalling outputs, not evidence that GPRC5C binds and activates a kinase. GPRC5A and GPRC5D differ from GPRC5B in partner interactions, while GPRC5C resembles GPRC5B in its dimerization pattern, so inheritance is plausible but unverified. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN001025902 · PTN001025902 UNRESOLVED Node seeded by GPRC5B (Q9NZH0) Fyn-activation evidence; Gprc5c is inside the clade but kinase activation has not been tested for it. Supporting Evidence: PMID:28228611 Gprc5c over expression in Huh7 cells was associated with increased ERK1/2 activity. PMID:42544579 Interestingly, coimmunoprecipitation experiments in HEK cells showed that GPRC5C has the same dimerization pattern as GPRC5B, whereas GPRC5A and GPRC5D differ strongly. |
| GO:0034451 centriolar satellite | ISO GO_REF:0000119 | UNDECIDED | Summary: Transferred from human GPRC5C. The human source annotation is no longer present in QuickGO (checked 2026-10-19), so the donor evidence cannot be traced. Reason: Mouse imaging places GPRC5C at the ciliary transition zone and basal region of olfactory cilia, not in centriolar satellites. Without the donor evidence this transfer cannot be assessed; it may reflect a since-withdrawn imaging annotation. Propagation Review Root cause: SOURCE STALE OR MISSING Sources checked: UniProtKB:Q9NQ84 · GPRC5C SOURCE STALE OR MISSING No centriolar satellite annotation on human GPRC5C in current QuickGO (checked 2026-10-19). Supporting Evidence: PMID:38110903 GPRC5C localization in sensory cilia parallels cilia formation and follows the formation of the basal body |
| GO:0035869 ciliary transition zone | ISO GO_REF:0000119 | ACCEPT | Summary: Supported directly in mouse olfactory sensory neurons by confocal and electron microscopy. Reason: Mouse data show GPRC5C at the transition zone of olfactory sensory cilia, where it affects the localization of the transition-zone protein MKS3 and of ciliary signalling proteins. Supporting Evidence: PMID:38110903 In closer examination, GPRC5C was found in the ciliary transition zone. PMID:38110903 GPRC5C localizes to the transition zone of sensory olfactory cilia extending from mature OSNs and affects the localization of MKS3, another transition zone protein. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA seeded by human GPRC5C's own IDA (PMID:23382219). Independently, GPRC5C forms heterodimers with the GPCRs AT1, EP2 and IP. Reason: The human source is a PX-FERM (SNX17/SNX27/SNX31) cargo-binding screen, which by itself does not show a signalling receptor complex. However, GPRC5C-AT1 heterodimers that facilitate angiotensin II binding are a receptor complex in the GO sense, so the term holds. It is a context-dependent location, kept as non-core. Supporting Evidence: PMID:42544579 The related receptor GPRC5C can also dimerize with prostanoid receptors IP and EP2, and, in addition, it interacts with the Angiotensin II (AngII) receptor AT1, resulting in a facilitation of ligand binding and AT1-dependent signaling (15). PMID:38597112 GPRC5C and the Ang II receptor AT1 dimerize |
| GO:0043235 signaling receptor complex | ISO PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | KEEP AS NON CORE | Summary: Transferred from human GPRC5C IDA based on a PX-FERM sorting nexin cargo screen that found GPCRs among SNX17/SNX27/SNX31 binders. The cached text does not show the GPRC5C-specific data. Reason: Consistent with the IBA row; the term is independently supported by GPRC5C-AT1 heterodimerization in smooth muscle. The PX-FERM screen supports endosomal sorting cargo status rather than a signalling complex, so the row is kept but not core. Supporting Evidence: PMID:23382219 These proteins include RTKs, integrins, GPCRs, hematocyte receptors, and phosphatases, among others. PMID:38597112 GPRC5C and the Ang II receptor AT1 dimerize |
| GO:0070062 extracellular exosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA from the GPRC5 node seeded by GPRC5B. Human GPRC5C also has HDA exosome annotations from vesicle proteomics, and GPRC5C is detected on circulating extracellular vesicles. Reason: Plausible for a plasma membrane protein shed in vesicles and consistent with proteomic data for the family, but not a site of its signalling function. Supporting Evidence: PMID:10945465 demonstrated RAIG-2 and RAIG-3 expression at the cell surface |
| GO:1902034 negative regulation of hematopoietic stem cell proliferation | IMP PMID:35725769 Hyaluronic acid-GPRC5C signalling promotes dormancy in haema... | NEW | Summary: Gprc5c-KO HSCs divide faster and lose quiescence; GPRC5C overexpression enhances quiescence; hyaluronic acid and NAG delay HSC division only when Gprc5c is present. Reason: GPRC5C is the receptor in the hyaluronic acid-GPRC5C signalling axis that keeps HSCs dormant, so it does part of the work of the process (signal reception), and both loss- and gain-of-function data point the same way. Regulation of HSC proliferation is a recurring, well-supported finding (also the basis of the Gprc5c dormancy reporter). Supporting Evidence: PMID:35725769 In vitro single-cell cultivation of HSCs confirmed that Gprc5c KO had an accelerated division rate compared with wild-type (WT) control PMID:35725769 However, in vitro HA and NAG treatment of Gprc5c-KO HSCs did not affect quiescence, in vitro self-renewal capacity or in vivo self-renewal capacity compared with WT HSCs PMID:35725769 GPRC5C OE led to enhanced quiescence as indicated by an increase of G0 cells, a slower first division rate and decreased CDK6 expression |
| GO:0001664 G protein-coupled receptor binding | IPI PMID:42544579 Small molecule inhibitor of orphan GPCR dimerization improve... | NEW | Summary: GPRC5C co-immunoprecipitates and dimerizes with the GPCRs AT1, EP2 and IP; mutating the conserved dimerization interface abolishes this. Reason: Heterodimerization with other GPCRs is the best-characterized mechanism by which GPRC5C acts (facilitating angiotensin II binding to AT1 and AT1 signalling in smooth muscle). GPCR binding is more informative than generic protein binding and is supported by interface-mutation and decoy-peptide data in mouse cells. Supporting Evidence: PMID:42544579 In summary, GPRC5C displays the same dimerization pattern as GPRC5B in HEK cells, and its inactivation in macrophages reproduces the hyperactivity phenotype observed in GPRC5B-deficient macrophages. PMID:38597112 GPRC5C and the Ang II receptor AT1 dimerize, and knockdown of GPRC5C resulted in reduced binding of Ang II to AT1 receptors PMID:42544579 The related receptor GPRC5C can also dimerize with prostanoid receptors IP and EP2, and, in addition, it interacts with the Angiotensin II (AngII) receptor AT1, resulting in a facilitation of ligand binding and AT1-dependent signaling (15). |
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Download this section (compressed HTML)Q: Should InterPro restrict IPR002956 (PRINTS PR01223, Bride of sevenless) so that it no longer matches mouse Gprc5c, or should InterPro2GO drop GO:0005118 and GO:0007601 from this family entry? The Gprc5c hit is two fingerprint segments on TM1 and TM6, and the human ortholog does not match.
Q: Is hyaluronic acid a direct orthosteric ligand of GPRC5C, or does it act through a co-receptor (for example CD44) that brings it close to GPRC5C?
Q: Does GPRC5C, like GPRC5B, activate Src-family kinases (supporting the inherited protein kinase activator activity IBA), or does its divergent C-terminal tail lack this function?
Experiment: Measure direct binding of defined-length hyaluronan oligosaccharides and NAG to purified GPRC5C (nanodisc SPR or radioligand/fluorescent-ligand binding), with mutations at the docking-predicted 7TM pocket and CD44 knockout cells as controls.
Hypothesis: Hyaluronic acid binds GPRC5C directly.
Experiment: Co-express mouse GPRC5C with ROS1 in trans (co-culture of expressing cells) and test for ROS1 phosphorylation and co-immunoprecipitation, with NELL2 as positive control, to formally exclude a BOSS-like sevenless-binding role.
Hypothesis: GPRC5C does not bind ROS1.
Experiment: Use G protein knockout HEK cells or BRET G protein sensors to identify which G protein family GPRC5C engages after hyaluronic acid or NAG stimulation.
Hypothesis: GPRC5C couples to Gq in HSCs.
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