MEN1-ZC3HC1 is one spoke-expanded BioPlex row in HCT116, and UniProt records ZC3HC1 weakly or not expressed in leukocytes - declined
also called menin-ZC3HC1 · menin-NIPA · EBI-54864551
A database lists ZC3HC1, a nuclear-envelope protein, as a menin partner. It rests on a single colon-cancer-cell experiment that never measured the pair directly, and the protein is barely present in blood cells at all.
The same thing, for a scientist
**Verdict: DECLINED.** The entire basis is IntAct record EBI-54864551: PMID 33961781 (BioPlex 3.0 / HCT116 arm), anti-tag co-immunoprecipitation, **spoke expansion**, HA-FLAG-ZC3HC1 as bait and MEN1 as prey, host **HCT116 colon carcinoma**, intact-miscore **0.35** - the lowest AP-MS score in this beat [E1]. One publication, one cell line, one pull-down, and the binary pair was **inferred, not measured** [E1]. Unlike CD226 this partner is compartment-compatible with menin: UniProt gives ZC3HC1 experimentally coded Nucleus and Nucleus envelope [E3]. **The relevance objection is the sharper one:** UniProt's tissue-specificity comment for ZC3HC1 ends *'Weakly or not expressed in leukocytes'* [E3], and this project's index disease is a leukaemia. **Criterion C2: fails (a) and (b); (c) does not apply.** **`confidence_overall` on this entry rates the INTERACTION, not the adjudication.** The adjudication is strong; the interaction is what is weak, and a reader scanning the field should see the weak thing.
The single record
EBI-54864551 ZC3HC1 (HA-Flag tandem tag, BAIT) <-> MEN1 (PREY)
detectionMethod anti tag coip
type association
expansionMethod spoke expansion
host Homo sapiens HCT116 colon carcinoma cell
publication 33961781 (BioPlex 3.0)
annotations ['figure legend (Supplementary table 1)']
intactMiscore 0.35
0.35 is the lowest miscore of the two AP-MS partners in this beat (CD226 scores 0.53 on each of its two rows). IntAct's MI-score folds in the number of publications, the number of distinct detection methods and the interaction type, so the value is largely a restatement of 'one paper, one method, spoke-expanded' rather than an independent judgement - but it is the database's own grade and it is low.
The association type, as distinct from physical association or direct interaction, is IntAct recording that the members were co-purified and nothing more.
Compartment does not decline this one; the disease does
It is worth separating two objections that would otherwise be blurred.
Compartment: compatible, and stated as such. ZC3HC1 - also called NIPA - is annotated to Nucleus and Nucleus envelope with experimental evidence 3. It is a component of the nuclear basket, recruited to the nuclear pore via TPR, and it is also an F-box protein of an SCF complex. Menin is nuclear. Nothing about location argues against this pair, and pretending otherwise would be borrowing an argument this entry does not have.
Expression in the index lineage: this is the real objection. UniProt's tissue-specificity comment reads: 'Widely expressed. Highly expressed in heart, skeletal muscle and testis. Expressed in brain, placenta, lung, kidney, liver, pancreas, spleen, thymus, prostate, ovary, small intestine and colon. Weakly or not expressed in leukocytes.' 3
A partner that is weakly or not expressed in the lineage this project studies is a low-value partner even if the interaction is real. That is a statement about priority, not about truth, and it is the honest reason this entry would remain low priority even if a second method appeared. It is also a caution: the UniProt comment is a curated summary of older expression work and is not a measurement in KMT2A-rearranged blasts, which nobody has made for this protein.
The F-box angle, and why it is a weaker version of the FBXW7 one
ZC3HC1/NIPA is an F-box protein that, with SKP1 and CUL1, forms an SCF ligase; its best-characterised substrate role concerns cyclin B1 and mitotic timing, and it is separately a structural component of the nuclear basket. So it is the third E3 substrate receptor among this beat's nine, after FBXW7 and SPOP.
The menin-turnover hypothesis that FBXW7 raises applies here too, but weaker, because ZC3HC1's substrate repertoire is narrow and well-studied and menin is not in it. The more likely reading is the artefactual arm of hyp-q128-three-of-menins-nine-declined-partners-are-e3-ligase-substrate-receptors: over-expressed substrate receptors are promiscuous in AP-MS, and a nuclear-basket protein pulled from whole-cell lysate will bring nuclear-envelope-adjacent material with it.
| partner a | gene-men1 |
|---|---|
| partner b | ZC3HC1 |
| partner b uniprot | Q86WB0 |
| partner b length AA | 502 |
| partner a uniprot | O00255 |
| partner a length AA | 610 |
| verdict | DECLINED |
| adjudicated by | Q128, cycle 91, 2026-09-23 |
| druggability | Not assessable. No region, residue or domain is mapped on either protein in any record, so it is not known whether the menin-inhibitor MBM pocket is involved, and no structure exists. |
| n methods | 1 |
| n platforms | 1 |
| expansion method | spoke expansion |
| intact miscore | 0.35 |
| absence class | never-measured |
| absence class note | No experiment has tested menin against ZC3HC1 in a haematopoietic cell, and UniProt's own tissue comment says the protein is weakly or not expressed there. No deposited dataset substitutes for this, so closing it needs wet work - and the lineage comment argues the work is not worth doing until something else points here. |
interface residues a
[]
structures
[]
ligands
[ "drug-revumenib", "drug-ziftomenib" ]
records
[ "EBI-54864551 (anti tag coip, HCT116, BioPlex 3.0)" ]
intact feature types
[ "tandem tag" ]
lineage relevance
{
"uniprot_tissue_comment": "Weakly or not expressed in leukocytes",
"index_disease_lineage": "haematopoietic",
"measured_in_kmt2a_r_blasts": false
}c2
{
"a_second_method": false,
"b_endogenous_side": false,
"c_wild_type": null,
"admitted": false,
"failing_clause": "a and b"
}- If menin has a nuclear-basket-associated pool, a menin inhibitor could perturb nucleocytoplasmic transport of something, and this project already tracks an export axis (XPO1) where that would matter. The row is far too weak to support that, but the question is not absurd and nothing rules it out.
- The lineage argument used to deprioritise this partner is itself a curated summary, not a measurement in the index disease. If it is wrong, the deprioritisation is wrong, and this entry would be the reason nobody looked again.
- Is ZC3HC1 protein detectable in KMT2A-rearranged blasts at all? The UniProt comment is a curated summary of older work; a single proteomics lookup in an existing leukaemia dataset would either close this partner permanently or reopen it.
- Does the nuclear basket contact menin at all? ZC3HC1 is a TPR-recruited basket component, and the broader question - whether menin or the KMT2A fusion has a nuclear-pore-proximal pool - is a localisation question this corpus has not asked.
- Is menin an SCF-ZC3HC1 substrate? Weakly motivated, but it is the same one-week experiment as the FBXW7 version and would be answered by the same reagents.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
IntAct record EBI-54864551 curates a MEN1-ZC3HC1 interaction from PMID 33961781 (BioPlex 3.0). Detection method anti-tag co-immunoprecipitation, interaction type 'association', expansion method SPOKE EXPANSION, host Homo sapiens HCT116 colon carcinoma cell, ZC3HC1 as HA-FLAG tandem-tagged BAIT and MEN1 as PREY, annotated to Supplementary Table 1. intact-miscore 0.35. No mutation is recorded on either side.
IntAct molecular interaction database, REST findInteractions on O00255, retrieved 2026-09-23 by Q128 · IntAct (EMBL-EBI) 2026What this evidence cannot show
Spoke expansion is the decisive caveat and it is in the row itself: the binary MEN1-ZC3HC1 pair was never measured. It was INFERRED by connecting every prey in a ZC3HC1 bait pull-down to the bait. IntAct records this honestly and a consumer that ignores the expansionMethod column converts an inference into a measurement. Read live from IntAct REST 2026-09-23; the BioPlex supplementary table was not opened.
Evidence that argues against this (1)
- BioPlex's own headline is that interactions are extensively cell-line-specific and that networks rewire between 293T and HCT116. A partner recovered once, in one line, as a spoke-expanded prey is precisely the class the paper says transfers least well - so the source argues against its own row being general. Huttlin EL et al. 2021
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
PMID 33961781 reports BioPlex 3.0: AP-MS of 10,128 human proteins in 293T cells giving 118,162 interactions among 14,586 proteins, plus a second network from 5,522 immunoprecipitations in HCT116 cells. Its stated headline is that interactions are extensively cell-line-specific and that subnetworks rewire between the two lines.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. · Huttlin EL, Bruckner RJ, Navarrete-Perea J, Cannon JR, Baltier K, Gebreab F, Gygi MP, Thornock A, et al. (28 authors), Gygi SP · Cell 2021What this evidence cannot show
Abstract read in full; the supplementary interaction tables were not opened, so the MEN1 row is taken from IntAct's curation of them rather than from the source table. BioPlex is a platform and a collaboration, not an independent observer: BioPlex 1.0, 2.0 and 3.0 share methods, reagents and personnel, and this project has already been caught counting two BioPlex releases as two publications.
Evidence that argues against this (1)
- BioPlex recovers an enormous number of real complexes and dismissing an AP-MS row on principle would discard most of the structured interactome. The objection here is specific - one line, one pull-down, spoke expansion, a bait that the line does not natively express - and it would not apply to a BioPlex row recovered reciprocally or in both cell lines. Huttlin EL et al. 2021
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
UniProtKB Q86WB0 (ZC3HC1) is 502 aa. Subcellular location: Nucleus (ECO:0000269), Nucleus envelope (ECO:0000269). Tissue specificity: Widely expressed. Highly expressed in heart, skeletal muscle and testis. Weakly or not expressed in leukocytes MEN1 (O00255, 610 aa) carries a single subcellular location, Nucleus, with experimental evidence (ECO:0000269), and tissue specificity 'Ubiquitous'.
UniProtKB entry Q86WB0, subcellular location and tissue specificity, retrieved 2026-09-23 · UniProt Consortium 2026What this evidence cannot show
UniProt subcellular-location comments are curated pointers, and rule 91 in this project's brief established that an ECO:0000269 code means a curator read AN experiment, not necessarily THE experiment or the best one. The cited papers behind these location lines were not opened here. Uncoded lines are recorded as uncoded and not discarded.
Evidence that argues against this (1)
- A compartment mismatch is a prior, not a refutation. Proteins move: menin's own UniProt record annotates only Nucleus, yet the founding localisation paper (PMID 9465067) maps at least two NLSs and UniProt does not cite it, which this project recorded as rule 91. An argument from UniProt compartments is therefore an argument from an incomplete record on both sides of the pair. UniProt Consortium 2026
IntAct-curated MEN1 partner, adjudicated DECLINED by Q128 (a and b)
per-partner adjudication of ZC3HC1
the cycle-72 summary entry this per-partner entry decomposes
the third substrate receptor, and the weakest row