id: Q92990
gene_symbol: GLMN
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Glomulin (GLMN; also known as FAP48/FAP68, FKBP-associated protein) is a
  ~68 kDa, predominantly alpha-helical cytoplasmic protein (with a HEAT-repeat-like
  architecture) that functions as a regulatory component of cullin-RING ubiquitin
  ligase (CRL/SCF) complexes. It binds directly to the RING domain of RBX1 (ROC1)
  through its C-terminal half and masks the surface that RBX1 uses to recruit the
  E2 ubiquitin-conjugating enzyme CDC34, thereby inhibiting RBX1-dependent E3
  ubiquitin ligase activity and blocking RBX1-mediated neddylation of CUL1.
  By sequestering RBX1, glomulin stabilizes assembled SCF/CRL components and
  controls the auto-ubiquitination and turnover of the F-box substrate receptor
  FBXW7, thereby influencing the abundance of FBXW7 substrates such as Cyclin E
  and c-Myc. Glomulin has been found in CRL/SCF assemblies containing RBX1 with
  CUL1, CUL2, CUL3, CUL4A, and in a CUL7-RBX1-SKP1-FBXW8 complex. Loss-of-function
  mutations in GLMN cause glomuvenous malformations, cutaneous venous lesions with
  abnormal smooth-muscle-like glomus cells, reflecting a requirement for glomulin
  in normal vascular development. An alternatively spliced shorter isoform
  (isoform 2, FAP48) was originally characterized as a ligand of the immunophilins
  FKBP12 (FKBP1A) and FKBP52 (FKBP4), and glomulin/FAP68 was also reported to bind
  the inactive hepatocyte growth factor receptor (MET) and modulate downstream
  p70 S6 kinase signaling; these immunophilin- and receptor-associated activities
  predate the discovery of the CRL-regulatory role and are mechanistically distinct
  from it. In innate immunity, glomulin also binds the RING domains of the cellular
  inhibitor of apoptosis proteins cIAP1 and cIAP2, inhibits their self-ubiquitination,
  and acts as a negative regulator of cIAP-mediated inflammasome activation and
  macrophage pyroptosis; the Shigella effector IpaH7.8 ubiquitinates glomulin to
  drive its degradation and enhance inflammation. Structurally, glomulin binds RBX1
  with high affinity (Kd in the nanomolar range) through a region in its C-terminal
  half (approximately residues 300-594) that occludes the RBX1 surface used to
  recruit the E2 enzyme CDC34.
alternative_products:
- name: 1 (FAP68, FKBP-associated protein 68 kDa)
  id: Q92990-1
- name: 2 (FAP48, FKBP-associated protein 48 kDa)
  id: Q92990-2
  sequence_note: VSP_008882, VSP_008883
existing_annotations:
- term:
    id: GO:0055105
    label: ubiquitin-protein transferase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of the core glomulin molecular function, inhibition of ubiquitin-protein transferase (E3 ligase) activity via RBX1 binding.
    action: ACCEPT
    reason: This is the experimentally established core molecular function of glomulin; it binds the RBX1 RING domain with high affinity (Kd ~38.6 nM, via a minimal region around residues 300-594) and masks the E2-binding surface, outcompeting the E2 CDC34 to inhibit ubiquitin chain synthesis by neddylated CUL1-RBX1/SCF complexes. This is a non-catalytic, inhibitory regulatory activity, not a ligase activity, consistent with the gene's biological role as a CRL assembly/activity regulator rather than an E3 ligase.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34
    - reference_id: file:human/GLMN/GLMN-deep-research-falcon.md
      supporting_text: GLMN **masks the E2-binding site** on RBX1, thereby **outcompeting** the E2 enzyme **CDC34** and **inhibiting ubiquitin chain synthesis** by neddylated CUL1–RBX1 and SCF complexes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Interaction with FKBP4 (FKBP52) captured in a quantitative chaperone interaction network. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real FKBP4 interaction but the bare protein binding term is uninformative per curation guidelines; the immunophilin association is a secondary, non-core property.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Interacts with FKBP4 and FKBP1A
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome capturing multiple glomulin partners (EFS, RBX1, FKBP4, PEX5, SNAI1). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real IntAct interactions (including the functionally important RBX1 partner) but bare protein binding is uninformative and not a core function statement.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: 'Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Cell-specific proteome-scale interactome capturing glomulin partners including RBX1 and FKBP4. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: 'Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523'
- term:
    id: GO:0032743
    label: positive regulation of interleukin-2 production
  evidence_type: IDA
  original_reference_id: PMID:12604780
  qualifier: acts_upstream_of_or_within
  review:
    summary: FAP48 (isoform 2)-FKBP complexes were reported to increase IL-2 production in a Jurkat T-cell overexpression model. A secondary, isoform-associated immunological role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the overexpression study but represents an older, isoform-2 (FAP48)/immunophilin-associated activity distinct from the core CRL-regulatory function; an overexpression phenotype rather than a direct molecular role.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: contrary to FK506, which blocks IL2 synthesis, we observed that FAP48-FKBP complexes increase IL2 production
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IDA
  original_reference_id: PMID:8955134
  qualifier: enables
  review:
    summary: This reference characterizes FAP48 binding to the immunophilins FKBP59/FKBP12, not to a signaling receptor; the signaling receptor binding term is not supported by this paper.
    action: UNDECIDED
    reason: The cited paper (PMID:8955134) documents FAP48 binding to FKBP59/FKBP12 (immunophilins, peptidyl-prolyl isomerases), not a signaling receptor. The MGC/MGI annotation to GO:0005102 appears mismatched to this reference; the better-supported receptor interaction (MET) is captured separately under GO:0005171. Cannot confirm signaling receptor binding from the available abstract, so deferring rather than removing an experimental annotation.
    supported_by:
    - reference_id: PMID:8955134
      supporting_text: a 48-kDa protein that specifically interacts with the peptidyl prolyl isomerase FK506-binding protein 59 (FKBP59) and also with the well known FKBP12
- term:
    id: GO:0005171
    label: hepatocyte growth factor receptor binding
  evidence_type: IDA
  original_reference_id: PMID:11571281
  qualifier: enables
  review:
    summary: Glomulin/FAP68 binds the intracellular tail of the inactive hepatocyte growth factor receptor (MET) and is released upon MET phosphorylation. A real but secondary interaction.
    action: KEEP_AS_NON_CORE
    reason: Directly demonstrated MET binding via yeast two-hybrid and co-immunoprecipitation, but this receptor association is a secondary role distinct from the core CRL/RBX1-regulatory function.
    supported_by:
    - reference_id: PMID:11571281
      supporting_text: FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:12604780
  qualifier: acts_upstream_of_or_within
  review:
    summary: Generic cell surface receptor signaling assignment from the T-cell activation/IL-2 study. Overly generic and tied to a secondary role.
    action: KEEP_AS_NON_CORE
    reason: The supporting study concerns FAP48 effects on T-cell activation/proliferation; this very general process term reflects a secondary immunological role, not the core CRL-regulatory function.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: a player in T cell activation that increases IL2 synthesis
- term:
    id: GO:0008285
    label: negative regulation of cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:12604780
  qualifier: acts_upstream_of_or_within
  review:
    summary: FAP48 overexpression inhibits proliferation of Jurkat T cells. A secondary, isoform-associated antiproliferative phenotype.
    action: KEEP_AS_NON_CORE
    reason: Supported by the overexpression phenotype, but reflects a secondary FAP48/immunophilin-context role rather than the core CRL-regulatory molecular function. Mechanistically may relate to FBXW7/Cyclin E-c-Myc control, but is not directly demonstrated as such here.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506
- term:
    id: GO:0031462
    label: Cul2-RING ubiquitin ligase complex
  evidence_type: IPI
  original_reference_id: PMID:22405651
  qualifier: part_of
  review:
    summary: Glomulin was identified in complexes containing RBX1 plus a cullin, including CUL2. Reflects glomulin association with CRL2 assemblies via RBX1.
    action: ACCEPT
    reason: Supported by the demonstration that glomulin is found in complexes containing RBX1 plus one of the cullins (CUL1, CUL2, CUL3, CUL4A); part_of a Cul2-RING complex is consistent with its RBX1-bridged CRL association.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
- term:
    id: GO:0031463
    label: Cul3-RING ubiquitin ligase complex
  evidence_type: IPI
  original_reference_id: PMID:22405651
  qualifier: part_of
  review:
    summary: Glomulin association with a CUL3-RBX1 CRL complex.
    action: ACCEPT
    reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL3.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IPI
  original_reference_id: PMID:22405651
  qualifier: part_of
  review:
    summary: Glomulin association with a CUL4A-RBX1 CRL complex.
    action: ACCEPT
    reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL4A.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
- term:
    id: GO:0031461
    label: cullin-RING ubiquitin ligase complex
  evidence_type: IPI
  original_reference_id: PMID:22405651
  qualifier: part_of
  review:
    summary: General cullin-RING ligase complex membership via RBX1 binding; the parent term covering glomulin's CRL associations.
    action: ACCEPT
    reason: Correct general complex membership; glomulin is a regulatory component of cullin-RING/SCF complexes through RBX1. This is the appropriate in_complex term for the core function.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IDA
  original_reference_id: PMID:22405651
  qualifier: enables
  review:
    summary: Glomulin binds directly to the RING-domain E3 ligase component RBX1. Captures the key binding event underlying its inhibitory function.
    action: ACCEPT
    reason: Directly demonstrated binding to RBX1 (the RING E3 component); this binding underlies the core inhibitory molecular function and is more informative than bare protein binding.
    supported_by:
    - reference_id: PMID:22405651
      supporting_text: Glomulin (Glmn), a protein found mutated in the vascular disorder glomuvenous malformation (GVM), binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity
- term:
    id: GO:0032434
    label: regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:22405651
  qualifier: acts_upstream_of_or_within
  review:
    summary: Glomulin loss alters CRL/proteasome-dependent turnover of FBXW7 (and consequently Cyclin E and c-Myc). Captures the downstream biological process glomulin regulates.
    action: ACCEPT
    reason: Supported by mutant-phenotype evidence that glomulin loss increases CRL/proteasome-dependent FBXW7 turnover; this is the core biological process glomulin regulates via CRL inhibition.
    supported_by:
    - reference_id: PMID:22405651
      supporting_text: The increased turnover of Fbw7 is dependent on CRL and proteasome activity, indicating that Glmn modulates the E3 activity of CRL1(Fbw7)
- term:
    id: GO:0055105
    label: ubiquitin-protein transferase inhibitor activity
  evidence_type: IGI
  original_reference_id: PMID:22405651
  qualifier: enables
  review:
    summary: Genetic-interaction (with RBX1) evidence for the core inhibitory molecular function of glomulin on E3 ligase activity.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; glomulin binding to RBX1 inhibits its E3 ubiquitin ligase activity and CDC34 recruitment.
    supported_by:
    - reference_id: PMID:22405651
      supporting_text: binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11164950
  qualifier: enables
  review:
    summary: Interaction with FKBP4 (FKBP52) and FKBP1A (FKBP12); a Pro219 mutation disrupts the interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the real immunophilin (FKBP) interaction but bare protein binding is uninformative; the FKBP association is a secondary, non-core property.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: "P->A: Loss of interaction with FKBP4 and FKBP1A."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12604780
  qualifier: enables
  review:
    summary: Interaction with FKBP4 captured in the FAP48 T-cell study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real FKBP4 interaction but bare protein binding is uninformative and not a core function.
    supported_by:
    - reference_id: file:human/GLMN/GLMN-uniprot.txt
      supporting_text: Interacts with FKBP4 and FKBP1A
- term:
    id: GO:0001570
    label: vasculogenesis
  evidence_type: IMP
  original_reference_id: PMID:11845407
  qualifier: involved_in
  review:
    summary: Loss-of-function GLMN mutations cause glomuvenous malformations with abnormal vascular smooth-muscle cells, implicating glomulin in normal vascular development. A genuine but downstream/physiological role.
    action: KEEP_AS_NON_CORE
    reason: Strongly supported by human genetics (loss-of-function mutations cause GVM); reflects an organismal/developmental consequence of the molecular CRL-regulatory function rather than the core molecular activity itself. UniProt notes essential role in vasculature development.
    supported_by:
    - reference_id: PMID:11845407
      supporting_text: glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins
- term:
    id: GO:0001819
    label: positive regulation of cytokine production
  evidence_type: IMP
  original_reference_id: PMID:12604780
  qualifier: involved_in
  review:
    summary: Generic parent of the IL-2 production phenotype seen on FAP48 overexpression. Secondary, isoform-associated immunological role.
    action: KEEP_AS_NON_CORE
    reason: Supported as a generic parent of the IL-2 result from the FAP48 overexpression study; a secondary role, and more general than the specific IL-2 annotation.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: FAP48-FKBP complexes increase IL2 production
- term:
    id: GO:0032743
    label: positive regulation of interleukin-2 production
  evidence_type: IMP
  original_reference_id: PMID:12604780
  qualifier: involved_in
  review:
    summary: FAP48 overexpression increases IL-2 production in Jurkat T cells. Secondary, isoform-associated immunological role (duplicate aspect of the IDA annotation above).
    action: KEEP_AS_NON_CORE
    reason: Supported by the overexpression phenotype but a secondary FAP48/immunophilin-context role distinct from the core CRL-regulatory function.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: FAP48-FKBP complexes increase IL2 production
- term:
    id: GO:0040029
    label: epigenetic regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:12604780
  qualifier: involved_in
  review:
    summary: The cited FAP48 T-cell study reports altered expression of argininosuccinate synthetase and Mxi1 on FAP48 overexpression but does not demonstrate an epigenetic mechanism; the term appears to over-interpret the data.
    action: UNDECIDED
    reason: The supporting paper shows changes in target protein levels (ASS, Mxi1) following FAP48 overexpression, but provides no evidence of an epigenetic (e.g., chromatin/DNA-methylation) mechanism. The mapping to GO:0040029 looks like an over-interpretation; deferring rather than removing an experimental annotation whose full text was not read.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: the expression levels of argininosuccinate synthetase and the Myc antagonist Mxi1 are modified by overexpression of FAP48
- term:
    id: GO:0042130
    label: negative regulation of T cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:12604780
  qualifier: involved_in
  review:
    summary: FAP48 overexpression inhibits proliferation of Jurkat T cells, consistent with negative regulation of T-cell proliferation. Secondary, isoform-associated role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the overexpression phenotype in T cells but a secondary FAP48-context role rather than the core CRL-regulatory function.
    supported_by:
    - reference_id: PMID:12604780
      supporting_text: overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506
- term:
    id: GO:0042692
    label: muscle cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:11845407
  qualifier: involved_in
  review:
    summary: GVM lesions show abnormal smooth-muscle-like glomus cells, suggesting glomulin contributes to (vascular smooth) muscle cell differentiation. A downstream developmental role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the GVM phenotype (abnormal vascular smooth-muscle-like cells) but a downstream developmental consequence of the molecular function, not the core activity.
    supported_by:
    - reference_id: PMID:11845407
      supporting_text: glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis
- term:
    id: GO:0005171
    label: hepatocyte growth factor receptor binding
  evidence_type: IPI
  original_reference_id: PMID:11571281
  qualifier: enables
  review:
    summary: IPI evidence (with MET, UniProtKB:P08581) for glomulin/FAP68 binding the hepatocyte growth factor receptor. Duplicate aspect of the IDA annotation above; a secondary interaction.
    action: KEEP_AS_NON_CORE
    reason: Directly supported MET interaction but a secondary role distinct from the core CRL/RBX1-regulatory function.
    supported_by:
    - reference_id: PMID:11571281
      supporting_text: FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor
- term:
    id: GO:0042327
    label: positive regulation of phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:11571281
  qualifier: involved_in
  review:
    summary: Free FAP68 stimulates the downstream kinase p70 S6 kinase (RPS6KB1), increasing its activity/phosphorylation. A secondary signaling role.
    action: KEEP_AS_NON_CORE
    reason: Supported by the demonstration that free FAP68 stimulates p70S6K downstream of MET; a secondary signaling role distinct from the core CRL-regulatory function. UniProt notes contribution to RPS6KB1 phosphorylation.
    supported_by:
    - reference_id: PMID:11571281
      supporting_text: Free FAP68 exerts a specific stimulatory activity toward the downstream target p70 S6 protein kinase (p70S6K)
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: PMID:11164950
  title: Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the
    interaction with FKBP12 and FKBP52.
  findings:
  - statement: A Pro219 mutation in FAP48 (glomulin isoform 2) disrupts its interaction with the immunophilins FKBP12 (FKBP1A) and FKBP52 (FKBP4).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Documents the FAP48-FKBP immunophilin interaction (secondary, non-core property); source of a bare protein binding annotation.
- id: PMID:11571281
  title: Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.
  findings:
  - statement: Glomulin/FAP68 (isoform 1) binds the C-terminal tail of the inactive (unphosphorylated/kinase-defective) MET receptor, is released upon MET phosphorylation, and free FAP68 stimulates the downstream kinase p70 S6 kinase.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes the secondary MET-binding and p70S6K-stimulatory roles; source of GO:0005171 and GO:0042327 annotations.
- id: PMID:11845407
  title: Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations
    ("glomangiomas").
  findings:
  - statement: Loss-of-function germline (and somatic second-hit) mutations in GLMN cause glomuvenous malformations, vascular lesions with abnormal smooth-muscle-like glomus cells, implicating glomulin in vascular smooth-muscle cell differentiation and vascular morphogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Disease-gene identification establishing glomulin's requirement for normal vascular development; source of vasculogenesis and muscle cell differentiation annotations.
- id: PMID:12604780
  title: The FKBP-associated protein FAP48 is an antiproliferative molecule and a
    player in T cell activation that increases IL2 synthesis.
  findings:
  - statement: Overexpression of FAP48 (glomulin isoform 2) inhibits proliferation of Jurkat T cells, alters levels of argininosuccinate synthetase and Mxi1, and FAP48-FKBP complexes increase IL-2 production.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of several secondary T-cell/IL-2 process annotations from an isoform-2 overexpression model; the GO:0040029 epigenetic-regulation mapping appears to over-interpret the protein-level changes reported.
- id: PMID:22405651
  title: The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin
    RING ligase-mediated turnover of Fbw7.
  findings:
  - statement: Glomulin binds directly to the RING domain of RBX1 and inhibits its E3 ubiquitin ligase activity; glomulin loss decreases FBXW7 (Fbw7) levels and increases Cyclin E and c-Myc, with the increased FBXW7 turnover dependent on CRL and proteasome activity, demonstrating that glomulin modulates CRL1(Fbw7) E3 activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study establishing glomulin as an RBX1-binding inhibitor and regulator of cullin-RING ligase activity; full text not in cache (abstract only), but supports the core MF, complex-membership, and process annotations.
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of
    cellular protein homeostasis pathways.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Chaperone interaction network; source of a bare protein binding (FKBP4) annotation.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of multiple bare protein binding annotations (including RBX1).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cell-specific interactome; source of bare protein binding annotations (RBX1, FKBP4).
- id: PMID:8955134
  title: FAP48, a new protein that forms specific complexes with both immunophilins
    FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin.
  findings:
  - statement: FAP48 (glomulin) specifically interacts with the immunophilins FKBP59 (FKBP52/FKBP4) and FKBP12 (FKBP1A); the complexes are dissociated by FK506 and rapamycin, suggesting FAP48 is a natural ligand of these FKBPs.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Original FAP48 cloning/FKBP-binding paper; documents immunophilin binding, not signaling receptor binding. The MGI GO:0005102 (signaling receptor binding) annotation cited to this paper appears mismatched to the abstract content.
- id: file:human/GLMN/GLMN-deep-research-falcon.md
  title: Falcon deep research report for human GLMN
  findings:
  - statement: Glomulin is a non-enzymatic, high-affinity inhibitor of RBX1-containing cullin-RING ligases (Kd ~38.6 nM), binding the RBX1 RING domain via a minimal region (residues ~300-594) and masking the E2-binding surface to outcompete the E2 enzyme CDC34 and block ubiquitin chain synthesis.
    supporting_text: GLMN binds RBX1 with **high affinity** (reported Kd ~**38.6 nM**) and a minimal RBX1-binding GLMN region mapped to residues **300–594**. (duda2012structureofa pages 7-9) - GLMN **masks the E2-binding site** on RBX1, thereby **outcompeting** the E2 enzyme **CDC34** and **inhibiting ubiquitin chain synthesis** by neddylated CUL1–RBX1 and SCF complexes.
  - statement: Glomulin is selective for RBX1 over RBX2 and associates with CUL1-containing SCF/CRL1 complexes and other cullins, with the best-supported pathway being CRL/SCF regulation, especially CRL1/SCF(FBW7).
    supporting_text: GLMN interacts selectively with **RBX1** and shows little/no interaction with **RBX2** in the cited biochemical/cell-based experiments.
  - statement: Beyond CRL regulation, glomulin binds the RING domains of cIAP1 and cIAP2, inhibits their self-ubiquitination, and acts as a negative regulator of cIAP-mediated inflammasome activation and macrophage pyroptosis; the Shigella effector IpaH7.8 ubiquitinates and degrades glomulin to enhance inflammation.
    supporting_text: GLMN binds **cIAP1 and cIAP2** via their **RING domains** and inhibits their **self-ubiquitination**. (suzuki2018shigellahijacksthe pages 1-2) - Modulating GLMN levels altered inflammasome responses; the authors conclude GLMN is a **negative regulator of cIAP-mediated inflammasome activation**.
  - statement: Glomulin shows stimulus-dependent localization near inflammasome structures, forming puncta that colocalize with active caspase-1 after LPS/ATP stimulation in macrophages.
    supporting_text: Upon LPS/ATP stimulation, **GLMN forms puncta that colocalize with active caspase-1**, and GLMN can colocalize with cIAP2 after Shigella infection, supporting a stimulus-dependent localization near inflammasome-associated structures.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Falcon (Edison Scientific) synthesis. The core RBX1-inhibitor mechanism is consistent with the cached Tron et al. 2012 abstract (PMID:22405651) and UniProt. The structural/affinity detail (Duda et al. 2012 Mol Cell, Kd ~38.6 nM, residues 300-594) and the cIAP/inflammasome axis (Suzuki et al. 2018 EMBO Reports) are author-year/DOI leads not previously in this review and not yet PMID-verified here; the cIAP-inflammasome function is surfaced as a proposed new term rather than added as a GO annotation.
core_functions:
- description: Regulatory component of cullin-RING/SCF E3 ubiquitin ligase complexes that binds directly to the RING domain of RBX1 and inhibits RBX1-dependent E3 ubiquitin ligase activity by masking its E2 (CDC34)-binding surface, thereby controlling CRL activity and the assembly/turnover of SCF components such as FBXW7.
  molecular_function:
    id: GO:0055105
    label: ubiquitin-protein transferase inhibitor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  in_complex:
    id: GO:0031461
    label: cullin-RING ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:22405651
    supporting_text: binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity
  - reference_id: file:human/GLMN/GLMN-uniprot.txt
    supporting_text: Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34
  directly_involved_in:
  - id: GO:0032434
    label: regulation of proteasomal ubiquitin-dependent protein catabolic process
- description: Binds the RBX1 RING-domain E3 ligase subunit, an interaction that stabilizes CRL/SCF components (FBXW7, RBX1, cullins) and blocks RBX1-mediated neddylation of CUL1, thereby regulating cullin-RING ligase-dependent proteasomal turnover of substrates including FBXW7 (and downstream Cyclin E and c-Myc).
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  locations:
  - id: GO:0005737
    label: cytoplasm
  in_complex:
    id: GO:0031461
    label: cullin-RING ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:22405651
    supporting_text: Loss of Glmn in a variety of cells, tissues, and GVM lesions results in decreased levels of Fbw7 and increased levels of Cyclin E and c-Myc
  - reference_id: file:human/GLMN/GLMN-uniprot.txt
    supporting_text: Required for normal stability and normal cellular levels of key components of SCF ubiquitin ligase complexes, including FBXW7, RBX1, CUL1, CUL2, CUL3, CUL4A
  directly_involved_in:
  - id: GO:0032434
    label: regulation of proteasomal ubiquitin-dependent protein catabolic process
proposed_new_terms:
- proposed_name: negative regulation of cIAP-mediated inflammasome activation
  proposed_definition: Any process that decreases the rate, frequency, or extent of inflammasome activation that is dependent on cellular inhibitor of apoptosis proteins (cIAP1/BIRC2, cIAP2/BIRC3), for example by a regulatory protein binding the cIAP RING domain and inhibiting cIAP self-ubiquitination.
  justification: Glomulin binds the RING domains of cIAP1 and cIAP2, inhibits their self-ubiquitination, and acts as a negative regulator of cIAP-mediated inflammasome activation and macrophage pyroptosis (Suzuki et al. 2018 EMBO Reports; the Shigella effector IpaH7.8 degrades glomulin to enhance inflammation). This innate-immunity function is mechanistically distinct from the CRL/SCF-regulatory role and is not captured by any existing GLMN GO annotation, representing a genuine gap. No sufficiently specific existing GO term was identified, so this is proposed without an invented GO ID.
  supported_by:
  - reference_id: file:human/GLMN/GLMN-deep-research-falcon.md
    supporting_text: GLMN binds **cIAP1 and cIAP2** via their **RING domains** and inhibits their **self-ubiquitination**. (suzuki2018shigellahijacksthe pages 1-2) - Modulating GLMN levels altered inflammasome responses; the authors conclude GLMN is a **negative regulator of cIAP-mediated inflammasome activation**.
- proposed_name: RING-type E3 ubiquitin ligase inhibitor activity
  proposed_definition: Binding to the RING domain of a RING-type ubiquitin-protein ligase and inhibiting its E3 ligase activity, for example by masking the surface used to recruit a ubiquitin-conjugating (E2) enzyme, thereby blocking ubiquitin transfer.
  justification: Glomulin's defining biochemical activity is direct binding to RING-domain E3 components (RBX1, and also cIAP1/cIAP2) with masking of the E2-binding surface. The existing GO:0055105 ubiquitin-protein transferase inhibitor activity captures the inhibition but a RING-specific, E2-masking inhibitor term would more precisely describe the structurally characterized mechanism (Duda et al. 2012). Proposed without an invented GO ID; may already be partially covered, listed for curator consideration.
  supported_by:
  - reference_id: file:human/GLMN/GLMN-deep-research-falcon.md
    supporting_text: GLMN **masks the E2-binding site** on RBX1, thereby **outcompeting** the E2 enzyme **CDC34** and **inhibiting ubiquitin chain synthesis** by neddylated CUL1–RBX1 and SCF complexes.
suggested_questions:
- question: How is glomulin's inhibition of RBX1/CRL activity relieved in cells (e.g., by neddylation status, CAND1-type exchange, or competing F-box receptors), and what signals trigger glomulin release from assembled CRLs?
- question: To what extent are glomulin's secondary roles (FKBP/immunophilin binding, MET receptor binding and p70S6K stimulation, T-cell IL-2 effects) mechanistically connected to its core CRL-regulatory function versus independent moonlighting activities?
- question: Does glomulin use the same RBX1-binding region (residues ~300-594, masking the E2/CDC34-binding surface) to engage the RING domains of cIAP1/cIAP2, and is the cIAP-inflammasome regulatory function genetically separable from the CRL-regulatory function in glomuvenous malformation versus innate-immune contexts?
suggested_experiments:
- description: Reconstitute SCF(FBXW7) ubiquitination in vitro with purified glomulin, RBX1, CUL1, SKP1, FBXW7, CDC34/UBE2R and NEDD8 machinery to quantify how glomulin inhibits CDC34 recruitment, neddylation, and FBXW7 auto-ubiquitination, including with GVM-associated and RBX1-binding-deficient (K425A/N476A/L567A/R574A) glomulin variants.
- description: Perform quantitative proteomics and CRL substrate-stability assays in GLMN-null versus wild-type cells (and in patient-derived GVM tissue) to define the cullin-RING ligase substrate repertoire stabilized or destabilized by glomulin loss across CUL1/2/3/4A complexes.
- description: In macrophages, test whether RBX1-binding-deficient glomulin variants retain cIAP1/cIAP2 binding and inhibition of cIAP self-ubiquitination, and measure inflammasome activation/caspase-1 puncta and pyroptosis upon GLMN depletion or Shigella IpaH7.8 expression, to map whether one binding surface mediates both CRL and cIAP regulation.