Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0055105 ubiquitin-protein transferase inhibitor activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of the core glomulin molecular function, inhibition of ubiquitin-protein transferase (E3 ligase) activity via RBX1 binding. 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. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34 file:human/GLMN/GLMN-deep-research-falcon.md 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.
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	KEEP AS NON CORE	Summary: Interaction with FKBP4 (FKBP52) captured in a quantitative chaperone interaction network. Bare protein binding is uninformative. 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. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Interacts with FKBP4 and FKBP1A
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: High-throughput binary interactome capturing multiple glomulin partners (EFS, RBX1, FKBP4, PEX5, SNAI1). Bare protein binding is uninformative. Reason: Real IntAct interactions (including the functionally important RBX1 partner) but bare protein binding is uninformative and not a core function statement. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: Cell-specific proteome-scale interactome capturing glomulin partners including RBX1 and FKBP4. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523
GO:0032743 positive regulation of interleukin-2 production	IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:12604780 contrary to FK506, which blocks IL2 synthesis, we observed that FAP48-FKBP complexes increase IL2 production
GO:0005102 signaling receptor binding	IDA PMID:8955134 FAP48, a new protein that forms specific complexes with both...	UNDECIDED	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. 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. Supporting Evidence: PMID:8955134 a 48-kDa protein that specifically interacts with the peptidyl prolyl isomerase FK506-binding protein 59 (FKBP59) and also with the well known FKBP12
GO:0005171 hepatocyte growth factor receptor binding	IDA PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:11571281 FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor
GO:0007166 cell surface receptor signaling pathway	IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: Generic cell surface receptor signaling assignment from the T-cell activation/IL-2 study. Overly generic and tied to a secondary role. 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. Supporting Evidence: PMID:12604780 a player in T cell activation that increases IL2 synthesis
GO:0008285 negative regulation of cell population proliferation	IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: FAP48 overexpression inhibits proliferation of Jurkat T cells. A secondary, isoform-associated antiproliferative phenotype. 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. Supporting Evidence: PMID:12604780 overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506
GO:0031462 Cul2-RING ubiquitin ligase complex	IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Glomulin was identified in complexes containing RBX1 plus a cullin, including CUL2. Reflects glomulin association with CRL2 assemblies via RBX1. 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. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
GO:0031463 Cul3-RING ubiquitin ligase complex	IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Glomulin association with a CUL3-RBX1 CRL complex. Reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL3. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex	IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Glomulin association with a CUL4A-RBX1 CRL complex. Reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL4A. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A
GO:0031461 cullin-RING ubiquitin ligase complex	IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: General cullin-RING ligase complex membership via RBX1 binding; the parent term covering glomulin's CRL associations. 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. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes
GO:0031625 ubiquitin protein ligase binding	IDA PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Glomulin binds directly to the RING-domain E3 ligase component RBX1. Captures the key binding event underlying its inhibitory function. 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. Supporting Evidence: PMID:22405651 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
GO:0032434 regulation of proteasomal ubiquitin-dependent protein catabolic process	IMP PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Glomulin loss alters CRL/proteasome-dependent turnover of FBXW7 (and consequently Cyclin E and c-Myc). Captures the downstream biological process glomulin regulates. 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. Supporting Evidence: PMID:22405651 The increased turnover of Fbw7 is dependent on CRL and proteasome activity, indicating that Glmn modulates the E3 activity of CRL1(Fbw7)
GO:0055105 ubiquitin-protein transferase inhibitor activity	IGI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and...	ACCEPT	Summary: Genetic-interaction (with RBX1) evidence for the core inhibitory molecular function of glomulin on E3 ligase activity. Reason: Core molecular function with direct experimental support; glomulin binding to RBX1 inhibits its E3 ubiquitin ligase activity and CDC34 recruitment. Supporting Evidence: PMID:22405651 binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity
GO:0005515 protein binding	IPI PMID:11164950 Mutation of FKBP associated protein 48 (FAP48) at proline 21...	KEEP AS NON CORE	Summary: Interaction with FKBP4 (FKBP52) and FKBP1A (FKBP12); a Pro219 mutation disrupts the interaction. Bare protein binding is uninformative. Reason: Records the real immunophilin (FKBP) interaction but bare protein binding is uninformative; the FKBP association is a secondary, non-core property. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt P->A: Loss of interaction with FKBP4 and FKBP1A.
GO:0005515 protein binding	IPI PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: Interaction with FKBP4 captured in the FAP48 T-cell study. Bare protein binding is uninformative. Reason: Real FKBP4 interaction but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Interacts with FKBP4 and FKBP1A
GO:0001570 vasculogenesis	IMP PMID:11845407 Mutations in a novel factor, glomulin, are responsible for g...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:11845407 glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins
GO:0001819 positive regulation of cytokine production	IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: Generic parent of the IL-2 production phenotype seen on FAP48 overexpression. Secondary, isoform-associated immunological role. 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. Supporting Evidence: PMID:12604780 FAP48-FKBP complexes increase IL2 production
GO:0032743 positive regulation of interleukin-2 production	IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: FAP48 overexpression increases IL-2 production in Jurkat T cells. Secondary, isoform-associated immunological role (duplicate aspect of the IDA annotation above). Reason: Supported by the overexpression phenotype but a secondary FAP48/immunophilin-context role distinct from the core CRL-regulatory function. Supporting Evidence: PMID:12604780 FAP48-FKBP complexes increase IL2 production
GO:0040029 epigenetic regulation of gene expression	IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	UNDECIDED	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. 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. Supporting Evidence: PMID:12604780 the expression levels of argininosuccinate synthetase and the Myc antagonist Mxi1 are modified by overexpression of FAP48
GO:0042130 negative regulation of T cell proliferation	IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo...	KEEP AS NON CORE	Summary: FAP48 overexpression inhibits proliferation of Jurkat T cells, consistent with negative regulation of T-cell proliferation. Secondary, isoform-associated role. Reason: Supported by the overexpression phenotype in T cells but a secondary FAP48-context role rather than the core CRL-regulatory function. Supporting Evidence: PMID:12604780 overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506
GO:0042692 muscle cell differentiation	IMP PMID:11845407 Mutations in a novel factor, glomulin, are responsible for g...	KEEP AS NON CORE	Summary: GVM lesions show abnormal smooth-muscle-like glomus cells, suggesting glomulin contributes to (vascular smooth) muscle cell differentiation. A downstream developmental role. 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. Supporting Evidence: PMID:11845407 glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis
GO:0005171 hepatocyte growth factor receptor binding	IPI PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f...	KEEP AS NON CORE	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. Reason: Directly supported MET interaction but a secondary role distinct from the core CRL/RBX1-regulatory function. Supporting Evidence: PMID:11571281 FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor
GO:0042327 positive regulation of phosphorylation	IDA PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f...	KEEP AS NON CORE	Summary: Free FAP68 stimulates the downstream kinase p70 S6 kinase (RPS6KB1), increasing its activity/phosphorylation. A secondary signaling role. 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. Supporting Evidence: PMID:11571281 Free FAP68 exerts a specific stimulatory activity toward the downstream target p70 S6 protein kinase (p70S6K)

Core Functions

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:

ubiquitin-protein transferase inhibitor activity

Directly Involved In:

regulation of proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

In Complex:

cullin-RING ubiquitin ligase complex

Supporting Evidence:

PMID:22405651
binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity
file:human/GLMN/GLMN-uniprot.txt
Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34

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:

ubiquitin protein ligase binding

Directly Involved In:

regulation of proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

cytoplasm

In Complex:

cullin-RING ubiquitin ligase complex

Supporting Evidence:

PMID:22405651
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
file:human/GLMN/GLMN-uniprot.txt
Required for normal stability and normal cellular levels of key components of SCF ubiquitin ligase complexes, including FBXW7, RBX1, CUL1, CUL2, CUL3, CUL4A

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

PMID:11164950

Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52.

A Pro219 mutation in FAP48 (glomulin isoform 2) disrupts its interaction with the immunophilins FKBP12 (FKBP1A) and FKBP52 (FKBP4).

PMID:11571281

Ligand-regulated binding of FAP68 to the hepatocyte growth factor receptor.

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.

PMID:11845407

Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas").

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.

PMID:12604780

The FKBP-associated protein FAP48 is an antiproliferative molecule and a player in T cell activation that increases IL2 synthesis.

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.

PMID:22405651

The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.

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.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:8955134

FAP48, a new protein that forms specific complexes with both immunophilins FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and rapamycin.

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.

file:human/GLMN/GLMN-deep-research-falcon.md

Falcon deep research report for human GLMN

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.

"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."
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).

"GLMN interacts selectively with **RBX1** and shows little/no interaction with **RBX2** in the cited biochemical/cell-based experiments."
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.

"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**."
Glomulin shows stimulus-dependent localization near inflammasome structures, forming puncta that colocalize with active caspase-1 after LPS/ATP stimulation in macrophages.

"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."

Suggested Experiments

Experiment: 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.

Experiment: 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.

Experiment: 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.

Deep Research

Falcon

(GLMN-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2 artifacts 2026-06-13T07:18:57.809005

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000016 The document contains several illustrations of the GLMN–RBX1–CUL1 complex and the mechanism by which GLMN inhibits the ligase by ma (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive research report: Human GLMN (Glomulin; UniProt Q92990)

Executive summary

Human GLMN encodes glomulin (also reported as FAP68/FAP48), a non-enzymatic regulator of ubiquitin E3 ligase signaling. The strongest mechanistic evidence supports a primary function as a high-affinity inhibitor of RBX1-containing Cullin–RING ligases (CRLs), including CUL1–RBX1 (SCF/CRL1) complexes, by sterically masking the E2-binding surface of the RBX1 RING domain. This suppression of CRL activity can modulate turnover of key regulators such as FBW7, with downstream impacts on levels of FBW7 substrates (e.g., Cyclin E, c-Myc) in glomuvenous malformation tissue. Separately, GLMN can bind the RING domains of cIAP1/2 and acts as a negative regulator of cIAP-mediated inflammasome activation, linking GLMN to innate immune pyroptosis control in macrophages. (tron2012theglomuvenousmalformation pages 1-2, suzuki2018shigellahijacksthe pages 1-2, duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)

1) Key concepts and definitions (current understanding)

1.1 Gene/protein identity verification (disambiguation)

The retrieved mechanistic literature explicitly uses GLMN = glomulin in a human disease context (glomuvenous malformations) and reports the aliases FAP68 and FAP48, consistent with the UniProt description for Q92990. (tron2012theglomuvenousmalformation pages 1-2, tron2012theglomuvenousmalformation pages 9-10)

1.2 Cullin–RING ligases (CRLs) and SCF complexes

CRLs are multi-subunit E3 ubiquitin ligases built around a cullin scaffold (e.g., CUL1) and a RING protein (RBX1 or RBX2) that recruits E2~Ub and catalyzes ubiquitin transfer to substrates. GLMN’s best-supported molecular role is as a regulator of these CRL assemblies—specifically those containing RBX1 rather than RBX2. (tron2012theglomuvenousmalformation pages 1-2, nguyen2017cullinringe3ubiquitin pages 6-8)

1.3 What type of “function” does GLMN have?

GLMN is not an enzyme with a defined catalytic reaction in the cited evidence. Instead, it acts as an inhibitory adaptor/regulator that modulates E3 ligase activity by protein–protein interactions with RING domains. (duda2012structureofa pages 1-2, tron2012theglomuvenousmalformation pages 1-2)

2) Molecular function, mechanism, and pathways

2.1 Core molecular function: inhibition of RBX1-containing CRLs (SCF/CRL1)

Two independent 2012 Molecular Cell studies provide convergent primary evidence that GLMN binds directly to the RBX1 RING domain and inhibits its E3 ligase function. (duda2012structureofa pages 7-9, tron2012theglomuvenousmalformation pages 1-2)

Mechanistic model (structural/biochemical):
- 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. (duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)

These findings strongly support GLMN’s primary biochemical role as an E2-access inhibitor for RBX1-dependent CRLs. (duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)

2.2 Interaction network and specificity

GLMN interacts selectively with RBX1 and shows little/no interaction with RBX2 in the cited biochemical/cell-based experiments. (tron2012theglomuvenousmalformation pages 1-2, nguyen2017cullinringe3ubiquitin pages 6-8)
GLMN associates with cullins including CUL1, and coprecipitation evidence supports association with CUL3 and CUL4A as well (and weakly with CUL2). (tron2012theglomuvenousmalformation pages 1-2)

2.3 Downstream pathway consequences: FBW7 turnover and substrate accumulation

A key mechanistic consequence described is regulation of CRL1/SCF^FBW7: loss of GLMN can alter FBW7 stability, and disease tissue evidence is consistent with dysregulated turnover leading to accumulation of FBW7 substrates such as Cyclin E and c-Myc. (duda2012structureofa pages 1-2, tron2012theglomuvenousmalformation pages 1-2)

2.4 Innate immunity axis: GLMN–cIAPs–inflammasome/pyroptosis

A primary experimental study in EMBO Reports (2018) connects GLMN to innate immune regulation:
- 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. (suzuki2018shigellahijacksthe pages 1-2)
- The bacterial effector Shigella IpaH7.8 ubiquitinates GLMN and promotes its degradation, enhancing inflammasome activation and macrophage pyroptosis, demonstrating a pathogen-exploitation mechanism. (suzuki2018shigellahijacksthe pages 1-2)

This provides a second, well-supported pathway context for GLMN beyond vascular development: RING-E3 regulation within innate immunity. (suzuki2018shigellahijacksthe pages 1-2)

3) Subcellular localization and where GLMN acts

Direct steady-state localization annotations were limited in the retrieved text evidence. However, in macrophages:
- 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. (suzuki2018shigellahijacksthe pages 1-2)

In the CRL/SCF context, the mechanism implies GLMN acts where RBX1-containing CRLs operate (cytosol/nucleus depending on CRL), but explicit compartment calls were not present in the extracted text snippets. (duda2012structureofa pages 1-2, tron2012theglomuvenousmalformation pages 1-2)

4) Disease relevance and real-world implementations

4.1 Glomuvenous malformations (GVM) and GLMN loss-of-function

GLMN loss-of-function is causally linked to glomuvenous malformations, a hereditary vascular disorder; mechanistic studies further connect disease to truncating mutations that remove the RBX1-binding region needed for CRL inhibition. (tron2012theglomuvenousmalformation pages 1-2, duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)

A disease-target aggregation in Open Targets lists GLMN associations including glomuvenous malformation and venous malformation, each supported by multiple evidence items in their knowledgebase view. (OpenTargets Search: -GLMN)

4.2 Diagnostics in practice (genetic testing)

A recent clinical case report illustrates current real-world diagnostic practice for familial GVM:
- Diagnosis incorporated clinical exam, imaging, histopathology, and multigene NGS panel testing, identifying a heterozygous truncating GLMN variant (c.1319G>A; p.Trp440*), with familial segregation. (brazao2025multiplebluishpapules pages 3-5)

4.3 Treatment/management implementations

Recent literature describes symptomatic/local lesion treatments:
- Nd:YAG laser was used with clinical improvement in a pediatric familial GVM presentation, with additional emphasis on genetic counseling and individualized surveillance. (brazao2025multiplebluishpapules pages 3-5)
- The same report notes other modalities used clinically across cases (surgery, sclerotherapy, laser) with variable efficacy. (brazao2025multiplebluishpapules pages 5-7)

For glomus tumors (which are related by historical gene discussions but clinically distinct entities), a 2023 review/case report emphasizes that definitive diagnosis requires histology and that complete excision often resolves pain, reflecting current standard-of-care management for localized glomus tumors. (cohen2023glomusextradigitaltumor pages 1-2)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2024: continued recognition of GLMN in inflammasome/pyroptosis signatures

A 2024 oncology bioinformatics study (Wilms’ tumor) states GLMN is a negative regulator of pyroptosis via regulation of cIAP-mediated inflammasome processes, consistent with the primary 2018 mechanistic model. This represents “downstream adoption” of the GLMN–cIAP–inflammasome concept into disease-signature work. (tron2012theglomuvenousmalformation pages 5-6)

5.2 2023: clinical emphasis on phenotypic variability and diagnostic delay in glomus tumors

A 2023 case report/review highlights that extradigital glomus tumors often lack cold sensitivity and can be misdiagnosed, reinforcing the need for histologic confirmation and supporting real-world diagnostic workflows. (cohen2023glomusextradigitaltumor pages 1-2)

Limitation: within the retrieved corpus available for full-text evidence extraction here, the most detailed molecular mechanism remains anchored in 2012–2018 primary studies; 2023–2024 sources in this retrieval set are more clinical/educational or computational and contain fewer new mechanistic details in the snippets available. (suzuki2018shigellahijacksthe pages 1-2, duda2012structureofa pages 1-2)

6) Quantitative statistics and data points (from retrieved studies)

GLMN–RBX1 affinity: Kd ~38.6 nM (high-affinity binding). (duda2012structureofa pages 7-9)
Minimal RBX1-binding region: GLMN residues 300–594 are sufficient for RBX1 binding/inhibition in the structural/biochemical assays. (duda2012structureofa pages 7-9)
Clinical lesion sizing (example): extradigital glomus tumor case reported lesion components of 5 mm patch and 2 mm papule; excision performed via 3-mm punch in that case. (cohen2023glomusextradigitaltumor pages 1-2)
Open Targets evidence counts: GLMN–glomuvenous malformation and GLMN–venous malformation entries show 5 evidence items each in the retrieved Open Targets view. (OpenTargets Search: -GLMN)

Not found in retrieved full-text snippets: population prevalence/incidence for GVM, mutation-spectrum frequencies across cohorts, or large-case-series outcomes for GLMN-specific disease; these likely exist in specialty reviews, but were not retrievable as full text here. (brazao2025multiplebluishpapules pages 3-5, brazao2025multiplebluishpapules pages 5-7)

7) Visual evidence: structural mechanism

Cropped figure panels from Duda et al. (2012) depict the GLMN–RBX1–CUL1 structure and schematic mechanism showing masking of the E2-binding surface on RBX1, supporting the inhibitory model described above. (duda2012structureofa media eee68c89, duda2012structureofa media 2408c9f3, duda2012structureofa media 5a032bc3)

8) Evidence synthesis and expert interpretation

Across structural biology, biochemical assays, cell-based interaction studies, and disease-tissue correlations, the most coherent “primary function” model for GLMN is:

1) Molecular role: RBX1-directed inhibitor of CRL ubiquitination (especially SCF/CRL1), acting by direct RING-domain engagement. (duda2012structureofa pages 1-2, duda2012structureofa pages 7-9, tron2012theglomuvenousmalformation pages 1-2)

2) Physiologic relevance: proper tuning of CRL activity is necessary for vascular homeostasis/development, and disruption (e.g., truncating GLMN variants) is linked to glomuvenous malformations. (tron2012theglomuvenousmalformation pages 1-2, duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)

3) Context-dependent extension: GLMN also restrains cIAP1/2 RING activity, influencing inflammasome activation and pyroptosis in innate immune contexts, and can be targeted by bacterial E3 ligases to promote inflammation. (suzuki2018shigellahijacksthe pages 1-2)

Summary table artifact

The following table consolidates the functional annotation elements (identity, mechanism, pathways, localization evidence, disease, and quantitative data) with direct citations.

Category	Evidence summary	Key citations
Protein identity/synonyms	GLMN in the cited literature refers to human glomulin, the glomuvenous malformation protein; a foundational mechanistic study explicitly notes the aliases FAP68 and FAP48 and uses human cell lines and a human GLMN clone, matching UniProt Q92990.	(tron2012theglomuvenousmalformation pages 1-2, tron2012theglomuvenousmalformation pages 9-10)
Molecular function	GLMN is a negative regulator of RBX1-containing cullin-RING E3 ubiquitin ligases rather than an enzyme with its own catalytic activity. It inhibits CRL/SCF ubiquitination reactions and stabilizes selected regulators such as FBW7 by restraining CRL-dependent turnover.	(duda2012structureofa pages 1-2, tron2012theglomuvenousmalformation pages 1-2, nguyen2017cullinringe3ubiquitin pages 6-8)
Mechanism	Structural and biochemical work shows GLMN binds the RBX1 RING domain and masks the E2-binding surface, outcompeting the E2 enzyme CDC34 and blocking ubiquitin chain synthesis. A minimal RBX1-binding region spanning GLMN residues 300–594 was sufficient for this inhibitory interaction.	(duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)
Key binding partners/complexes	Direct and selective interaction with RBX1 is strongly supported, with little or no binding to RBX2 in the cited studies. GLMN associates with CUL1-containing SCF/CRL1 complexes and also with other cullins (including CUL3 and CUL4A in coprecipitation assays), and in innate immunity it binds cIAP1 and cIAP2 via their RING domains.	(tron2012theglomuvenousmalformation pages 1-2, duda2012structureofa pages 7-9, suzuki2018shigellahijacksthe pages 1-2)
Pathways	The best-supported pathway assignment is ubiquitin-proteasome regulation through CRL/SCF complexes, especially CRL1/SCF^FBW7. Additional evidence places GLMN in a GLMN–cIAP–inflammasome axis, where it negatively regulates cIAP-mediated inflammasome activation and thereby modulates pyroptosis.	(suzuki2018shigellahijacksthe pages 1-2, duda2012structureofa pages 1-2, suzuki2018shigellahijacksthe pages 12-13, tron2012theglomuvenousmalformation pages 1-2)
Subcellular localization	Specific steady-state compartment annotation is limited in the gathered evidence. In macrophages, GLMN formed puncta after LPS/ATP stimulation that colocalized with active caspase-1, and it colocalized with cIAP2 after Shigella infection, supporting stimulus-dependent localization near inflammasome-related structures.	(suzuki2018shigellahijacksthe pages 1-2)
Disease relevance	Loss-of-function GLMN mutations are causally linked to glomuvenous malformation (GVM), and mechanistic studies connect disease to disruption of the RBX1-binding/inhibitory function of GLMN. GVM patient samples also showed accumulation of FBW7 substrates such as Cyclin E and c-Myc, consistent with altered CRL regulation in disease tissue.	(tron2012theglomuvenousmalformation pages 1-2, duda2012structureofa pages 1-2, OpenTargets Search: -GLMN)
Key quantitative data	Reported quantitative measurements include high-affinity GLMN–RBX1 binding with Kd ~38.6 nM and mapping of a minimal RBX1-binding fragment to GLMN residues 300–594. Open Targets evidence also lists GLMN associations with glomuvenous malformation and venous malformation, each supported by 5 evidence items in the retrieved dataset.	(duda2012structureofa pages 7-9, OpenTargets Search: -GLMN)

Table: This table summarizes the best-supported functional annotation for human GLMN/glomulin from the gathered mechanistic and disease evidence. It highlights identity, molecular mechanism, pathway placement, localization evidence, disease links, and key quantitative findings relevant to UniProt Q92990.

Key sources (publication date, URL)

Tron AE et al. Molecular Cell (Apr 2012). “The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.” https://doi.org/10.1016/j.molcel.2012.02.005 (tron2012theglomuvenousmalformation pages 1-2)
Duda DM et al. Molecular Cell (Aug 2012). “Structure of a glomulin–RBX1–CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface.” https://doi.org/10.1016/j.molcel.2012.05.044 (duda2012structureofa pages 1-2, duda2012structureofa pages 7-9)
Suzuki S et al. EMBO Reports (Jan 2018). “Shigella hijacks the glomulin–cIAPs–inflammasome axis to promote inflammation.” https://doi.org/10.15252/embr.201643841 (suzuki2018shigellahijacksthe pages 1-2)
Cohen PR. Cureus (May 2023). “Glomus Extradigital Tumor… Comprehensive Review of Glomus Tumors.” https://doi.org/10.7759/cureus.38737 (cohen2023glomusextradigitaltumor pages 1-2)
Brazao C et al. Dermatology Online Journal (May 2025). “Multiple bluish papules and nodules… diagnostic challenge.” https://doi.org/10.5070/d331265296 (brazao2025multiplebluishpapules pages 3-5)

References

(tron2012theglomuvenousmalformation pages 1-2): Adriana E. Tron, Takehiro Arai, David M. Duda, Hiroshi Kuwabara, Jennifer L. Olszewski, Yuko Fujiwara, Brittany N. Bahamon, Sabina Signoretti, Brenda A. Schulman, and James A. DeCaprio. The glomuvenous malformation protein glomulin binds rbx1 and regulates cullin ring ligase-mediated turnover of fbw7. Molecular cell, 46 1:67-78, Apr 2012. URL: https://doi.org/10.1016/j.molcel.2012.02.005, doi:10.1016/j.molcel.2012.02.005. This article has 78 citations and is from a highest quality peer-reviewed journal.
(suzuki2018shigellahijacksthe pages 1-2): Shiho Suzuki, Toshihiko Suzuki, Hitomi Mimuro, Tsunehiro Mizushima, and Chihiro Sasakawa. Shigella hijacks the glomulin–ciaps–inflammasome axis to promote inflammation. EMBO reports, 19:101-89, Jan 2018. URL: https://doi.org/10.15252/embr.201643841, doi:10.15252/embr.201643841. This article has 33 citations and is from a highest quality peer-reviewed journal.
(duda2012structureofa pages 1-2): David M. Duda, Jennifer L. Olszewski, Adriana E. Tron, Michal Hammel, Lester J. Lambert, M. Brett Waddell, Tanja Mittag, James A. DeCaprio, and Brenda A. Schulman. Structure of a glomulin-rbx1-cul1 complex: inhibition of a ring e3 ligase through masking of its e2-binding surface. Molecular cell, 47 3:371-82, Aug 2012. URL: https://doi.org/10.1016/j.molcel.2012.05.044, doi:10.1016/j.molcel.2012.05.044. This article has 94 citations and is from a highest quality peer-reviewed journal.
(duda2012structureofa pages 7-9): David M. Duda, Jennifer L. Olszewski, Adriana E. Tron, Michal Hammel, Lester J. Lambert, M. Brett Waddell, Tanja Mittag, James A. DeCaprio, and Brenda A. Schulman. Structure of a glomulin-rbx1-cul1 complex: inhibition of a ring e3 ligase through masking of its e2-binding surface. Molecular cell, 47 3:371-82, Aug 2012. URL: https://doi.org/10.1016/j.molcel.2012.05.044, doi:10.1016/j.molcel.2012.05.044. This article has 94 citations and is from a highest quality peer-reviewed journal.
(tron2012theglomuvenousmalformation pages 9-10): Adriana E. Tron, Takehiro Arai, David M. Duda, Hiroshi Kuwabara, Jennifer L. Olszewski, Yuko Fujiwara, Brittany N. Bahamon, Sabina Signoretti, Brenda A. Schulman, and James A. DeCaprio. The glomuvenous malformation protein glomulin binds rbx1 and regulates cullin ring ligase-mediated turnover of fbw7. Molecular cell, 46 1:67-78, Apr 2012. URL: https://doi.org/10.1016/j.molcel.2012.02.005, doi:10.1016/j.molcel.2012.02.005. This article has 78 citations and is from a highest quality peer-reviewed journal.
(nguyen2017cullinringe3ubiquitin pages 6-8): Henry C. Nguyen, Wei Wang, and Yong Xiong. Cullin-ring e3 ubiquitin ligases: bridges to destruction. Sub-cellular biochemistry, 83:323-347, Jan 2017. URL: https://doi.org/10.1007/978-3-319-46503-6_12, doi:10.1007/978-3-319-46503-6_12. This article has 143 citations.
(OpenTargets Search: -GLMN): Open Targets Query (-GLMN, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(brazao2025multiplebluishpapules pages 3-5): Claudia Brazao, Dora Mancha, Lanyu Sun, Sofia Antunes-Duarte, Sonia Fernandes, Luis Rodrigues, Marcia Rodrigues, Pedro De Vasconcelos, Luis Soares-de-Almeida, and Paulo Filipe. Multiple bluish papules and nodules in a 12-year-old child with lower gastrointestinal bleeding: a diagnostic challenge. Dermatology Online Journal, May 2025. URL: https://doi.org/10.5070/d331265296, doi:10.5070/d331265296. This article has 0 citations and is from a peer-reviewed journal.
(brazao2025multiplebluishpapules pages 5-7): Claudia Brazao, Dora Mancha, Lanyu Sun, Sofia Antunes-Duarte, Sonia Fernandes, Luis Rodrigues, Marcia Rodrigues, Pedro De Vasconcelos, Luis Soares-de-Almeida, and Paulo Filipe. Multiple bluish papules and nodules in a 12-year-old child with lower gastrointestinal bleeding: a diagnostic challenge. Dermatology Online Journal, May 2025. URL: https://doi.org/10.5070/d331265296, doi:10.5070/d331265296. This article has 0 citations and is from a peer-reviewed journal.
(cohen2023glomusextradigitaltumor pages 1-2): Philip R. Cohen. Glomus extradigital tumor: a case report of an extradigital glomus tumor on the wrist and comprehensive review of glomus tumors. Cureus, May 2023. URL: https://doi.org/10.7759/cureus.38737, doi:10.7759/cureus.38737. This article has 17 citations.
(tron2012theglomuvenousmalformation pages 5-6): Adriana E. Tron, Takehiro Arai, David M. Duda, Hiroshi Kuwabara, Jennifer L. Olszewski, Yuko Fujiwara, Brittany N. Bahamon, Sabina Signoretti, Brenda A. Schulman, and James A. DeCaprio. The glomuvenous malformation protein glomulin binds rbx1 and regulates cullin ring ligase-mediated turnover of fbw7. Molecular cell, 46 1:67-78, Apr 2012. URL: https://doi.org/10.1016/j.molcel.2012.02.005, doi:10.1016/j.molcel.2012.02.005. This article has 78 citations and is from a highest quality peer-reviewed journal.
(duda2012structureofa media eee68c89): David M. Duda, Jennifer L. Olszewski, Adriana E. Tron, Michal Hammel, Lester J. Lambert, M. Brett Waddell, Tanja Mittag, James A. DeCaprio, and Brenda A. Schulman. Structure of a glomulin-rbx1-cul1 complex: inhibition of a ring e3 ligase through masking of its e2-binding surface. Molecular cell, 47 3:371-82, Aug 2012. URL: https://doi.org/10.1016/j.molcel.2012.05.044, doi:10.1016/j.molcel.2012.05.044. This article has 94 citations and is from a highest quality peer-reviewed journal.
(duda2012structureofa media 2408c9f3): David M. Duda, Jennifer L. Olszewski, Adriana E. Tron, Michal Hammel, Lester J. Lambert, M. Brett Waddell, Tanja Mittag, James A. DeCaprio, and Brenda A. Schulman. Structure of a glomulin-rbx1-cul1 complex: inhibition of a ring e3 ligase through masking of its e2-binding surface. Molecular cell, 47 3:371-82, Aug 2012. URL: https://doi.org/10.1016/j.molcel.2012.05.044, doi:10.1016/j.molcel.2012.05.044. This article has 94 citations and is from a highest quality peer-reviewed journal.
(duda2012structureofa media 5a032bc3): David M. Duda, Jennifer L. Olszewski, Adriana E. Tron, Michal Hammel, Lester J. Lambert, M. Brett Waddell, Tanja Mittag, James A. DeCaprio, and Brenda A. Schulman. Structure of a glomulin-rbx1-cul1 complex: inhibition of a ring e3 ligase through masking of its e2-binding surface. Molecular cell, 47 3:371-82, Aug 2012. URL: https://doi.org/10.1016/j.molcel.2012.05.044, doi:10.1016/j.molcel.2012.05.044. This article has 94 citations and is from a highest quality peer-reviewed journal.
(suzuki2018shigellahijacksthe pages 12-13): Shiho Suzuki, Toshihiko Suzuki, Hitomi Mimuro, Tsunehiro Mizushima, and Chihiro Sasakawa. Shigella hijacks the glomulin–ciaps–inflammasome axis to promote inflammation. EMBO reports, 19:101-89, Jan 2018. URL: https://doi.org/10.15252/embr.201643841, doi:10.15252/embr.201643841. This article has 33 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

duda2012structureofa pages 7-9
tron2012theglomuvenousmalformation pages 1-2
suzuki2018shigellahijacksthe pages 1-2
brazao2025multiplebluishpapules pages 3-5
brazao2025multiplebluishpapules pages 5-7
cohen2023glomusextradigitaltumor pages 1-2
tron2012theglomuvenousmalformation pages 5-6
duda2012structureofa pages 1-2
tron2012theglomuvenousmalformation pages 9-10
suzuki2018shigellahijacksthe pages 12-13
https://doi.org/10.1016/j.molcel.2012.02.005
https://doi.org/10.1016/j.molcel.2012.05.044
https://doi.org/10.15252/embr.201643841
https://doi.org/10.7759/cureus.38737
https://doi.org/10.5070/d331265296
https://doi.org/10.1016/j.molcel.2012.02.005,
https://doi.org/10.15252/embr.201643841,
https://doi.org/10.1016/j.molcel.2012.05.044,
https://doi.org/10.1007/978-3-319-46503-6_12,
https://doi.org/10.5070/d331265296,
https://doi.org/10.7759/cureus.38737,

📚 Additional Documentation

Pn Notes

(GLMN-pn-notes.md)

GLMN PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q92990
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/GLMN/GLMN-ai-review.yaml
AIGR review HTML: missing - genes/human/GLMN/GLMN-ai-review.html
Gene notes: missing - genes/human/GLMN/GLMN-notes.md
GOA TSV: present - genes/human/GLMN/GLMN-goa.tsv
UniProt record: present - genes/human/GLMN/GLMN-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/GLMN.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/GLMN.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/GLMN/GLMN-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 16; UNDECIDED: 2

PN Consistency Summary

Consistency: Strong agreement across deep research (falcon, HIGH), review YAML, and dossier. Glomulin is a non-catalytic high-affinity RBX1-binding inhibitor (Kd ~38.6 nM, residues ~300-594) that masks the CDC34/E2 surface and inhibits CRL/SCF E3 activity, controlling FBXW7 turnover (Tron/Tron 2012 PMID:22405651; Duda 2012). Directionality (inhibitor) is consistent everywhere. All 33 GOA rows reviewed. No catalytic-ligase term assigned (correct).
PN story / NEW pressure: The core inhibitory function is already well captured in GOA — GO:0055105 ubiquitin-protein transferase inhibitor activity (IBA+IGI, ACCEPT), GO:0031625 ubiquitin protein ligase binding, and CRL complex memberships. The review surfaces a genuine GO gap: the cIAP1/cIAP2-inflammasome axis (Suzuki 2018), proposed as a new term without an invented ID (correct). GO:0141086 negative regulation of inflammasome-mediated signaling pathway exists (verified real) and is a reasonable existing anchor for that proposed term.
Evidence alignment: Convergent on the keystone paper: PN cites PMID:22405651, which is also the foundational, HIGH-relevance reference driving the review's core MF/BP/complex annotations. Review adds the older FAP48/FAP68 immunophilin and MET literature (8955134, 11164950, 11571281, 12604780, 11845407) as non-core, plus interactome PMIDs — all marked secondary; no conflict with the PN story.
Verdict: Fully consistent; PN inhibitor mapping (GO:1904667) is well-aligned with the review (GO:0055105) — no over-reach, no missing-NEW pressure on the core function. Recommended edits: [YAML] optional — anchor the proposed "negative regulation of cIAP-mediated inflammasome activation" term to the now-existing GO:0141086 (verify scope) as the closest existing parent/match. No mapping change required.

Full Consistency Review

UniProt: Q92990 · batch: proteostasis-batch-2026-06-13 · review status: COMPLETE
PN placement: UPS|E3 ubiquitin and UBL ligases|CRL regulator|CRL inhibitor ; PN-node mapping: type mapped, scope=ok_for_propagation_to_go, GO:1904667 negative regulation of ubiquitin protein ligase activity (group/class context_only; branch no_mapping)
Consistency: Strong agreement across deep research (falcon, HIGH), review YAML, and dossier. Glomulin is a non-catalytic high-affinity RBX1-binding inhibitor (Kd ~38.6 nM, residues ~300-594) that masks the CDC34/E2 surface and inhibits CRL/SCF E3 activity, controlling FBXW7 turnover (Tron/Tron 2012 PMID:22405651; Duda 2012). Directionality (inhibitor) is consistent everywhere. All 33 GOA rows reviewed. No catalytic-ligase term assigned (correct).
PN story / NEW pressure: The core inhibitory function is already well captured in GOA — GO:0055105 ubiquitin-protein transferase inhibitor activity (IBA+IGI, ACCEPT), GO:0031625 ubiquitin protein ligase binding, and CRL complex memberships. The review surfaces a genuine GO gap: the cIAP1/cIAP2-inflammasome axis (Suzuki 2018), proposed as a new term without an invented ID (correct). GO:0141086 negative regulation of inflammasome-mediated signaling pathway exists (verified real) and is a reasonable existing anchor for that proposed term.
Mapping strategy: Sound. PN GO:1904667 (BP, negative regulation of ubiquitin protein ligase activity — verified) is the regulation-side counterpart of the review's MF GO:0055105; both are correct and complementary in directionality. Not over-broad like the TOMM20/HSPA8/RAB7A precedents — it is specifically the negative/inhibitor sense, matching the "CRL inhibitor" type.
Evidence alignment: Convergent on the keystone paper: PN cites PMID:22405651, which is also the foundational, HIGH-relevance reference driving the review's core MF/BP/complex annotations. Review adds the older FAP48/FAP68 immunophilin and MET literature (8955134, 11164950, 11571281, 12604780, 11845407) as non-core, plus interactome PMIDs — all marked secondary; no conflict with the PN story.
Verdict: Fully consistent; PN inhibitor mapping (GO:1904667) is well-aligned with the review (GO:0055105) — no over-reach, no missing-NEW pressure on the core function. Recommended edits: [YAML] optional — anchor the proposed "negative regulation of cIAP-mediated inflammasome activation" term to the now-existing GO:0141086 (verify scope) as the closest existing parent/match. No mapping change required.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/GLMN/GLMN-ai-review.yaml
PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | CRL regulator | CRL inhibitor

UniProt: Q92990
In branches: UPS
Signature domains: (none)
Auxiliary domains: (none)
PN references (titles):
- 22748924
PN-node mapping records (path + ancestors):
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|CRL inhibitor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:1904667 negative regulation of ubiquitin protein ligase activity]
  rationale: This PN type captures cullin-RING ligase inhibitors. The matching GO process target is negative regulation of ubiquitin protein ligase activity.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator
  status=context_only scope=too_broad_to_propagate GO=[GO:1904666 regulation of ubiquitin protein ligase activity]
  rationale: This PN group records regulation of cullin-RING ligase systems, but the members include inhibitors, exchange factors, and modulators with different directionality. It is context only.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:1904667 negative regulation of ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|CRL regulator|CRL inhibitor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

GLMN

Gene Description

Proposed New Ontology Terms

negative regulation of cIAP-mediated inflammasome activation

RING-type E3 ubiquitin ligase inhibitor activity

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive research report: Human GLMN (Glomulin; UniProt Q92990)

Executive summary

1) Key concepts and definitions (current understanding)

1.1 Gene/protein identity verification (disambiguation)

1.2 Cullin–RING ligases (CRLs) and SCF complexes

1.3 What type of “function” does GLMN have?

2) Molecular function, mechanism, and pathways

2.1 Core molecular function: inhibition of RBX1-containing CRLs (SCF/CRL1)

2.2 Interaction network and specificity

2.3 Downstream pathway consequences: FBW7 turnover and substrate accumulation

2.4 Innate immunity axis: GLMN–cIAPs–inflammasome/pyroptosis

3) Subcellular localization and where GLMN acts

4) Disease relevance and real-world implementations

4.1 Glomuvenous malformations (GVM) and GLMN loss-of-function

4.2 Diagnostics in practice (genetic testing)

4.3 Treatment/management implementations

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2024: continued recognition of GLMN in inflammasome/pyroptosis signatures

5.2 2023: clinical emphasis on phenotypic variability and diagnostic delay in glomus tumors

6) Quantitative statistics and data points (from retrieved studies)

7) Visual evidence: structural mechanism

8) Evidence synthesis and expert interpretation

Summary table artifact

Key sources (publication date, URL)

Artifacts

Citations

📚 Additional Documentation

Pn Notes

GLMN PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | CRL regulator | CRL inhibitor

Projected GO annotations (1)

Note

📄 View Raw YAML