GPR101 encodes an orphan class A/rhodopsin-like G protein-coupled receptor. The protein is a multi-pass plasma-membrane receptor with no firmly established endogenous ligand, but evolutionary and structural features support a GPCR signaling role. Increased GPR101 dosage is associated with X-linked acrogigantism and growth hormone-secreting pituitary adenoma predisposition, consistent with altered pituitary signaling rather than a defined enzymatic activity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004930 G protein-coupled receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: GPR101 is a seven-transmembrane rhodopsin-like orphan receptor; GPCR activity is the best-supported molecular-function annotation even though its endogenous ligand remains unknown. Reason: The UniProt record describes GPR101 as an orphan receptor and places it in the G-protein coupled receptor 1 family, and the IBA/InterPro evidence is consistent with the rhodopsin-like 7TM architecture. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt FUNCTION: Orphan receptor. file:human/GPR101/GPR101-uniprot.txt Belongs to the G-protein coupled receptor 1 family. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: GPR101 is a multi-pass plasma-membrane receptor, so plasma membrane localization is appropriate. Reason: The protein is curated by UniProt as a cell-membrane, multi-pass membrane protein and has a GPCR transmembrane architecture. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. |
| GO:0043410 positive regulation of MAPK cascade | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Positive regulation of MAPK cascade is plausible for GPCR signaling but is downstream and not specifically established as the core molecular function of orphan GPR101. Reason: The annotation is phylogenetically inferred from GPCR models rather than direct GPR101 ligand/signaling experiments in this review set. It should not be treated as a core gene function until receptor coupling and downstream pathway usage are better defined. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt FUNCTION: Orphan receptor. |
| GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: The current term is too specific because it names adrenergic receptor signaling, whereas GPR101 is an orphan GPCR and not an adrenergic receptor. Reason: If an adenylate-cyclase activating GPCR pathway annotation is retained from phylogenetic inference, the broader non-adrenergic term is more accurate for GPR101. Proposed replacements: adenylate cyclase-activating G protein-coupled receptor signaling pathway Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt FUNCTION: Orphan receptor. file:human/GPR101/GPR101-uniprot.txt Belongs to the G-protein coupled receptor 1 family. |
| GO:0004930 G protein-coupled receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: GPR101 is a seven-transmembrane rhodopsin-like orphan receptor; GPCR activity is the best-supported molecular-function annotation even though its endogenous ligand remains unknown. Reason: The UniProt record describes GPR101 as an orphan receptor and places it in the G-protein coupled receptor 1 family, and the IBA/InterPro evidence is consistent with the rhodopsin-like 7TM architecture. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt FUNCTION: Orphan receptor. file:human/GPR101/GPR101-uniprot.txt Belongs to the G-protein coupled receptor 1 family. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: GPR101 is a multi-pass plasma-membrane receptor, so plasma membrane localization is appropriate. Reason: The protein is curated by UniProt as a cell-membrane, multi-pass membrane protein and has a GPCR transmembrane architecture. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: The broad GPCR signaling pathway term is appropriate for a rhodopsin-like orphan GPCR. Reason: The annotation is broad enough to reflect receptor-family inference without over-specifying ligand or downstream transducer. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt Belongs to the G-protein coupled receptor 1 family. |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Membrane localization is correct but less informative than plasma membrane for this multi-pass receptor. Reason: Retain as a true broad cellular-component annotation; plasma membrane is the preferred core location. Supporting Evidence: file:human/GPR101/GPR101-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: This high-throughput HuRI interaction annotation records generic protein binding and does not define GPR101 molecular function. Reason: Protein binding is too vague for curation here. The source is a reference interactome map; it is useful interaction context but not a specific functional assignment for GPR101. Supporting Evidence: PMID:32296183 contains 52,569 verified PPIs involving 8,275 proteins |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | MARK AS OVER ANNOTATED | Summary: The source paper concerns PX-FERM cargo recognition and broad receptor trafficking, but the review evidence does not establish GPR101 as a stable signaling receptor complex component. Reason: A GPCR can be part of signaling assemblies, but this annotation is too generic and indirect for GPR101 core function. Supporting Evidence: PMID:23382219 These proteins include RTKs, integrins, GPCRs, hematocyte receptors, and phosphatases, among others. |
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Download this section (compressed HTML)Q: What endogenous ligand or ligand-independent activation mechanism drives GPR101 signaling in pituitary and hypothalamic contexts?
Q: Does human GPR101 activate Gs/adenylate cyclase directly, or are MAPK and cAMP pathway annotations indirect consequences of receptor overexpression?
Experiment: Measure cAMP, calcium, beta-arrestin recruitment, and ERK activation in cells expressing wild-type and disease-associated GPR101 dosage models.
Hypothesis: GPR101 dosage changes will reveal a specific GPCR coupling signature relevant to X-linked acrogigantism.
Experiment: Use pituitary-relevant cell models to test whether GPR101 perturbation alters GH/GHRH pathway outputs through a specific G protein coupling mechanism.
Hypothesis: Pituitary-relevant GPR101 signaling will connect receptor activity to GH pathway output.
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