GPRC5D (RAIG4) is an orphan class C (metabotropic glutamate receptor-like) seven-transmembrane G protein-coupled receptor of group 5, with no identified physiological ligand. It is a multi-pass plasma-membrane protein whose expression in normal tissue is largely restricted to the hair follicle, where it is implicated in hard keratin expression and hair and nail development. GPRC5D forms homodimers. Because its protein is strongly and selectively expressed at the surface of malignant plasma cells in multiple myeloma, independent of BCMA, it has become a leading cell-surface target for CAR T-cell and bispecific-antibody immunotherapy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Generic GPCR activity from InterPro. Reason: GPRC5D is a family C GPCR; no ligand or more specific activity has been established, so the general receptor term is as precise as the evidence allows. Supporting Evidence: PMID:11311935 which we assign to group 5 of family C GPCRs |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005515 protein binding | IPI PMID:39083597 Multiplexed mapping of the interactome of GPCRs with recepto... | REMOVE | Summary: Generic protein binding from high-throughput interactome and RAMP screens. Reason: Bare protein binding is uninformative under the protein-binding policy; the membrane-yeast-two-hybrid (HuRI) and RAMP partners are not tied to a defined function. Removal does not dispute the interactions. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane inherited from the GPRC5 family node. Reason: Matches direct evidence. Supporting Evidence: PMID:11311935 GPRC5D has seven putative transmembrane segments and is expressed in the cell membrane. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: GPRC5D is a seven-transmembrane plasma-membrane receptor. Reason: Multi-pass membrane protein at the cell surface; a validated surface antigen on myeloma cells. Supporting Evidence: PMID:11311935 GPRC5D has seven putative transmembrane segments and is expressed in the cell membrane. PMID:30918115 we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA |
| GO:0005886 plasma membrane | NAS PMID:11311935 Cloning and characterization of a human orphan family C G-pr... | ACCEPT | Summary: Cloning paper reports cell-membrane expression. Reason: GPRC5D is expressed in the cell membrane. Supporting Evidence: PMID:11311935 GPRC5D has seven putative transmembrane segments and is expressed in the cell membrane. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: GPCR signaling pathway from InterPro. Reason: GPRC5D is a GPCR; no downstream coupling is characterized, so the general pathway term is retained. Supporting Evidence: PMID:11311935 which we assign to group 5 of family C GPCRs |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: Generic membrane. Reason: Correct but too general; plasma membrane is the specific supported location already annotated. Proposed replacements: plasma membrane Supporting Evidence: PMID:11311935 GPRC5D has seven putative transmembrane segments and is expressed in the cell membrane. |
| GO:0030295 protein kinase activator activity | IBA GO_REF:0000033 | UNDECIDED | Summary: Protein kinase activator activity inherited from the GPRC5 family node. Reason: The assertion comes from the GPRC5 family node (donors GPRC5A/GPRC5B), which have reported kinase-modulating roles, but there is no GPRC5D-specific evidence for protein kinase activator activity, and the orphan receptor's signaling is uncharacterized. Propagation Review Root cause: UNRESOLVED Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001025902 UNRESOLVED GPRC5 family node; protein kinase activator activity rests on GPRC5A/GPRC5B evidence and its retention in orphan GPRC5D is not established. UniProtKB:Q9NZH0 SUPPORTS SOURCE BUT NOT TARGET GPRC5B donor contributing the family assertion; does not establish the activity in GPRC5D. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Signaling receptor complex inherited from the GPRC5 family node. Reason: GPRC5D homodimerizes; participation in a broader signaling complex is plausible but uncharacterized. |
| GO:0070062 extracellular exosome | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Extracellular exosome inherited from the family node. Reason: High-throughput style localization inherited from paralogs; a membrane protein may partition into extracellular vesicles but this is not a functional site. |
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Download this section (compressed HTML)Q: What is the endogenous ligand of GPRC5D and which G protein(s) does it couple to in hair follicle cells?
Q: Does GPRC5D have any signaling function in myeloma plasma cells, or is its relevance there purely as a surface antigen?
Experiment: Deorphanization screen (G-protein and arrestin biosensors) for GPRC5D, and knockout in keratinocyte/hair follicle organoids to define its role in hard keratin expression.
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