Oncofusion

start / graph / interface-menin-egfr-declined-single-bret-neoppi

Interfaceweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q128-the-menin-interactome-that-is-not-chromatin

MEN1-EGFR is ONE BRET well from the extended-driver arm of a mutation screen, for L858R only - declined

also called menin-EGFR · EGFR L858R neoPPI · EBI-63960130

A database lists EGFR, the lung-cancer receptor, as a menin partner. It rests on one well in an automated screen, using the mutant EGFR L858R, and EGFR sits in the cell membrane while menin sits in the nucleus.

The same thing, for a scientist

**Verdict: DECLINED.** The evidence is IntAct record EBI-63960130 and nothing else: one BRET measurement, PMID 35512704, HEK293T, NanoLuc-EGFR L858R donor and Venus-MEN1 acceptor, type 'proximity', annotated to supplementary **Table S6** - the extended-driver arm of the primary screen - intact-miscore **0.27** [E1]. The EGFR feature is `P00533:p.Leu858Arg`, typed **`mutation causing an interaction`** [E1]. This resolves to substitution level an allele that cycle 72 could only place at residue 858, and does so from the IntAct REST feature string rather than from recall. Menin appears nowhere in the paper's prose [E2]. **The compartment argument is weaker than it looks and is reported as such:** EGFR's dominant annotation is single-pass plasma membrane, but UniProt also carries **Nucleus with ECO:0000269** for EGFR [E3], so 'a receptor cannot meet a nuclear protein' is not available as a clean refutation. **Criterion C2: fails (a), (b) and (c).** **`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.

Go deeper
The record, and what Table S6 is
EBI-63960130   MEN1 (Venus, acceptor)  <->  EGFR (NanoLuc, donor)
  detectionMethod  bret
  type             proximity
  host             Homo sapiens HEK293T embryonic kidney cell
  featureShortLabelsB  ['P00533:p.Leu858Arg', 'nluc tag']
  featureTypesB        ['mutation causing', 'nluc']
  annotations          ['figure legend (ST6)']
  intactMiscore    0.27

ST6 is Table S6: qHT-dS screening and data analysis for the extended driver genes and mutations, i.e. a second sweep of the same BRET platform over more drivers. It is the primary screen output for that sweep - raw BRET saturation data and CARINA calls - with no orthogonal arm attached to it in the paper. PTEN's menin row comes from the same table.

So EGFR and PTEN are not merely single-method; they are single-method from the extension of the screen, which is one further step from any validation.

The compartment objection, stated honestly and then weakened

EGFR is a 1,210-residue single-pass type I membrane receptor. Menin is annotated to one compartment, Nucleus, with experimental evidence. On the face of it this is the least plausible pair in the beat.

But UniProt P00533 carries Nucleus at ECO:0000269, plus nuclear-membrane and Golgi lines (uncoded) 3. Nuclear EGFR is a genuine, if contested, literature. Rule 91 in this project's brief is explicit that an ECO:0000269 code means a curator read an experiment and not necessarily a good one, and the papers behind that line were not opened here - so this cuts both ways and neither way hard.

The conclusion is that the compartment argument is a prior and not a refutation, and this entry does not lean on it. The decline rests on: one BRET well, one publication, a mutant allele, a screen-output table, and total absence from the paper's prose. That is enough on its own, and borrowing a compartment argument that does not hold would weaken rather than strengthen the verdict.

Facts and figures
partner agene-men1
partner bEGFR
partner b uniprotP00533
partner b length AA1210
partner a uniprotO00255
partner a length AA610
verdictDECLINED
adjudicated byQ128, cycle 91, 2026-09-23
druggabilityNot 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.
alleleP00533:p.Leu858Arg
n methods1
intact miscore0.27
source panelTable S6, extended-driver arm of the primary screen
closesthe residue-only EGFR entry in ana-menin-neoppi-trap-ten-intact-partners-from-one-mutation-screen; the substitution is L858R
absence classmeasured-not-reported
absence class noteWild-type EGFR versus L858R BRET against MEN1 was measured and is in Mo et al. Table S6(A) inside PMC9597701, unread by this project. The separate question - does endogenous menin meet endogenous EGFR in any cell - is never-measured.
interface residues a
[]
structures
[]
ligands
[
  "drug-revumenib",
  "drug-ziftomenib"
]
records
[
  "EBI-63960130 (bret, HEK293T)"
]
intact feature types
[
  "mutation causing"
]
c2
{
  "a_second_method": false,
  "b_endogenous_side": false,
  "c_wild_type": false,
  "admitted": false,
  "failing_clause": "a, b and c"
}
How this could bite us back
  • An EGFR-inhibitor plus menin-inhibitor rationale would be the obvious misuse of this row, and the allele it rests on - L858R - is a lung adenocarcinoma lesion absent from KMT2A-rearranged leukaemia.
  • If menin genuinely had a membrane-proximal or cytoplasmic pool, a menin inhibitor's toxicity profile would have a component nobody attributes to it. The trials monitor differentiation syndrome and QTc; nothing in them would detect an off-chromatin menin effect, and this entry's decline should not be read as evidence that no such pool exists.
Still open
  1. What is the wild-type EGFR BRET value against MEN1 in Table S6(A)? The 'mutation causing' type is an assertion about that number and the number has never been read here.
  2. Is the reported proximity a nuclear-EGFR phenomenon or a cytoplasmic-menin phenomenon? BRET cannot say, and no imaging accompanies the row. A single co-localisation experiment in an L858R line would settle which compartment, if either, the signal comes from.
  3. Nuclear EGFR has its own chromatin literature. Has anyone asked whether nuclear EGFR and menin occupy overlapping loci, as opposed to forming a complex? That is a ChIP question and is cheaper than a co-IP.
Every source behind this entry (3)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    IntAct record(s) EBI-63960130 (bret, HEK293T) curate a MEN1-EGFR interaction from PMID 35512704. Detection method bioluminescence resonance energy transfer (BRET), interaction type 'proximity', host Homo sapiens HEK293T embryonic kidney cell, both partners epitope-tagged (NanoLuc donor on EGFR, Venus acceptor on MEN1). The EGFR side carries feature(s) P00533:p.Leu858Arg, typed by IntAct as 'mutation causing'. The row is annotated to Table S6, extended-driver arm of the primary screen of the paper. intact-miscore 0.27.

    What this evidence cannot show

    Read live from the IntAct REST endpoint on 2026-09-23; field names quoted are the REST JSON's own. A miscore of 0.27 is low on IntAct's 0-1 scale and is what a single-method, single-publication row scores by construction, so it is a restatement of the evidence thinness rather than an independent grade of it. The underlying supplementary table was not parsed; the allele and feature type are IntAct's curation of it.

    Evidence that argues against this (1)
    • IntAct's featureType vocabulary is the curator's reading of the paper, not the paper's own words. 'mutation causing an interaction' (MI:2227) and 'mutation with no effect' (MI:2226) both presuppose that a wild-type comparison was made and interpreted. If IntAct has typed a row wrongly, every verdict built on the type is wrong in the same direction, and the only way to check is the paper's own supplementary table. Mo X et al. 2022
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    PMID 35512704 is a quantitative high-throughput differential BRET screen (qHT-dS) of 17,792 wild-type/mutant interaction pairs in live HEK293T cells, built specifically to find interactions a cancer mutation creates and the parental protein does not make. In its 198,614-character PMC full text (PMC9597701), 'menin' and 'MEN1' occur exactly twice and both are the same key-resources row for a ThermoFisher anti-menin antibody (PA5-79663, RRID:AB_2746778). Menin is discussed in no sentence of the narrative, results or discussion.

    Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. · Mo X, Niu Q, Ivanov AA, Tsang YH, Tang C, Shu C, Li Q, Qian K, Wahafu A, Doyle SP, Cicka D, Yang X, Fan D, Reyna MA, Cooper LAD, Moreno CS, Zhou W, Owonikoko TK, Lonial S, Khuri FR, Du Y, Ramalingam SS, Mills GB, Fu H · Cell 2022
    PMID 35512704DOI
    What this evidence cannot show

    Full text retrieved by efetch db=pmc and searched after tag-stripping and entity unescaping, so a mention inside a figure image is invisible to it - and one is: MEN1 is a blotted row in Figure 4D. The supplementary tables that hold every menin number in this paper were not parsed. So 'menin is absent from the paper' would be false; the defensible claim is that menin is absent from the paper's prose.

    Evidence that argues against this (1)
    • A proximity or affinity signal measured between two tagged, co-overexpressed proteins in a heterologous cell line is a real measurement and is not a demonstration that the complex forms at endogenous stoichiometry in any tissue. The Mo et al. platform is explicitly a co-expression BRET screen in live HEK293T cells, and its own validation arm exists because the primary screen output is a candidate list, not a partner list. Mo X et al. 2022
  3. E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UniProtKB P00533 (EGFR) is 1210 aa. Subcellular location: Cell membrane single-pass type I (ECO:0000269), Endoplasmic reticulum membrane (ECO:0000269), Endosome (ECO:0000269), Nucleus (ECO:0000269), plus uncoded Golgi apparatus membrane, Nucleus membrane, Endosome membrane and Secreted lines. Tissue specificity: Ubiquitously expressed MEN1 (O00255, 610 aa) carries a single subcellular location, Nucleus, with experimental evidence (ECO:0000269), and tissue specificity 'Ubiquitous'.

    What 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
Connected to