id: Q96P66
gene_symbol: GPR101
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
existing_annotations:
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'FUNCTION: Orphan receptor.'
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: Belongs to the G-protein coupled receptor 1 family.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: GPR101 is a multi-pass plasma-membrane receptor, so plasma membrane localization
      is appropriate.
    action: ACCEPT
    reason: The protein is curated by UniProt as a cell-membrane, multi-pass membrane protein
      and has a GPCR transmembrane architecture.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.'
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'FUNCTION: Orphan receptor.'
- term:
    id: GO:0071880
    label: adenylate cyclase-activating adrenergic receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: The current term is too specific because it names adrenergic receptor signaling,
      whereas GPR101 is an orphan GPCR and not an adrenergic receptor.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'FUNCTION: Orphan receptor.'
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: Belongs to the G-protein coupled receptor 1 family.
- term:
    id: GO:0004930
    label: G protein-coupled receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'FUNCTION: Orphan receptor.'
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: Belongs to the G-protein coupled receptor 1 family.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: GPR101 is a multi-pass plasma-membrane receptor, so plasma membrane localization
      is appropriate.
    action: ACCEPT
    reason: The protein is curated by UniProt as a cell-membrane, multi-pass membrane protein
      and has a GPCR transmembrane architecture.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.'
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: The broad GPCR signaling pathway term is appropriate for a rhodopsin-like orphan
      GPCR.
    action: ACCEPT
    reason: The annotation is broad enough to reflect receptor-family inference without over-specifying
      ligand or downstream transducer.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: Belongs to the G-protein coupled receptor 1 family.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Membrane localization is correct but less informative than plasma membrane for this
      multi-pass receptor.
    action: KEEP_AS_NON_CORE
    reason: Retain as a true broad cellular-component annotation; plasma membrane is the preferred
      core location.
    supported_by:
    - reference_id: file:human/GPR101/GPR101-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: This high-throughput HuRI interaction annotation records generic protein binding
      and does not define GPR101 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: contains 52,569 verified PPIs involving 8,275 proteins
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: IDA
  original_reference_id: PMID:23382219
  qualifier: part_of
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: A GPCR can be part of signaling assemblies, but this annotation is too generic and
      indirect for GPR101 core function.
    supported_by:
    - reference_id: PMID:23382219
      supporting_text: These proteins include RTKs, integrins, GPCRs, hematocyte receptors, and
        phosphatases, among others.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: PMID:23382219
  title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM
    proteins.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: file:human/GPR101/GPR101-uniprot.txt
  title: UniProt record for GPR101
  findings: []
core_functions:
- molecular_function:
    id: GO:0004930
    label: G protein-coupled receptor activity
  description: GPR101 functions as an orphan class A GPCR at the plasma membrane, with receptor-family
    evidence supporting GPCR signaling while ligand identity and exact coupling specificity remain
    unresolved.
  directly_involved_in:
  - id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: file:human/GPR101/GPR101-uniprot.txt
    supporting_text: 'FUNCTION: Orphan receptor.'
  - reference_id: file:human/GPR101/GPR101-uniprot.txt
    supporting_text: 'SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.'
proposed_new_terms: []
suggested_questions:
- question: What endogenous ligand or ligand-independent activation mechanism drives GPR101 signaling
    in pituitary and hypothalamic contexts?
- question: Does human GPR101 activate Gs/adenylate cyclase directly, or are MAPK and cAMP pathway
    annotations indirect consequences of receptor overexpression?
suggested_experiments:
- description: 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.
- description: 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.