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start / graph / interface-menin-akt1-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Interfaceweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q128-the-menin-interactome-that-is-not-chromatin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-AKT1 is ONE BRET well from a mutation screen, for the E17K allele only - declined

also called menin-AKT1 · AKT1 E17K neoPPI · EBI-63961482

A database lists AKT1, a central growth-signalling kinase, as a menin partner. The entire basis is a single well in one automated screen, testing the mutant AKT1 E17K rather than the normal protein.

The same thing, for a scientist

**Verdict: DECLINED.** The whole evidence base is IntAct record EBI-63961482: one BRET measurement, PMID 35512704, HEK293T, NanoLuc-AKT1 E17K as donor and Venus-MEN1 as acceptor, interaction type 'proximity', annotated to supplementary **Table S2(B)** - the raw CARINA output of the primary screen - with intact-miscore **0.27** [E1]. The AKT1 side carries `P31749:p.Glu17Lys`, typed by IntAct as **`mutation causing an interaction`**, so the row asserts a gain created by the allele; wild-type AKT1 is not claimed to bind menin [E1]. Menin appears nowhere in the paper's prose [E2], and MEN1 is not identifiable among the labelled nodes of the AKT1 E17K spoke diagram in Figure 4F, which is where the paper's own validated AKT1 hits are drawn. Compartment does **not** argue against this one: UniProt gives AKT1 an experimentally coded nuclear pool [E3], so the objection here is method and allele, not location. **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
What the single record actually says
EBI-63961482   MEN1 (Venus, acceptor)  <->  AKT1 (NanoLuc, donor)
  detectionMethod  bret
  type             proximity
  host             Homo sapiens HEK293T embryonic kidney cell
  featureShortLabelsA  ['P31749:p.Glu17Lys', 'nluc tag']
  featureTypesA        ['mutation causing', 'nluc']
  featureShortLabelsB  ['venus tag']
  annotations          ['figure legend (ST2B)']
  intactMiscore    0.27

Three things are worth reading off that block rather than summarising.

type: proximity, not physical association. IntAct types BRET as proximity because energy transfer reports that two fluorophores are within roughly 10 nm, which a shared complex, a shared condensate or crowding in an overexpressing cell will all produce.

annotations: figure legend (ST2B). This is the primary screen's own output table, not a validation panel. The paper has a validation arm - GST pull-down, NanoPCA, semi-IP, co-IP - and menin is in none of it except on the BRAF row.

mutation causing. IntAct's MI:2227. The row's meaning is E17K created this, which makes it a statement about AKT1, not about menin.

Why the compartment argument does not help here, and saying so is the point

It would be convenient to decline AKT1 on localisation, and it would be wrong. UniProt P31749 carries Nucleus with ECO:0000269 - experimental evidence - alongside cytoplasm, cell membrane and mitochondrial intermembrane space 3. Nuclear AKT1 is a real, reported pool. Menin is nuclear. So the two proteins can be in the same compartment and the decline rests entirely on the thinness of the assay. Recording that explicitly matters, because a decline that quietly borrows a second argument it does not have is how a weak verdict becomes an overstated one.

AKT1 E17K is itself a membrane-recruitment allele: the PH-domain substitution increases phosphoinositide binding and drives AKT1 to the plasma membrane. A gain-of-proximity to a nuclear protein is not the direction that allele's known biology predicts, which is a reason for more scepticism about the row, not less.

Facts and figures
partner agene-men1
partner bAKT1
partner b uniprotP31749
partner b length AA480
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.
alleleP31749:p.Glu17Lys
n methods1
intact miscore0.27
source panelTable S2(B), primary screen CARINA output
absence classmeasured-not-reported
absence class noteThe wild-type AKT1 versus E17K BRET values against MEN1 were both measured by the qHT-dS platform and sit in Mo et al. Table S2(A) inside PMC9597701. Reading them is an afternoon and would say whether this is a gain from nothing or a small change on a constitutive over-expression signal.
interface residues a
[]
structures
[]
ligands
[
  "drug-revumenib",
  "drug-ziftomenib"
]
records
[
  "EBI-63961482 (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
  • A menin inhibitor plus an AKT or PI3K inhibitor is an obvious-looking combination, and this database row is exactly the sort of thing that would be cited for it. The row is one well, for a mutant allele, in kidney cells - it cannot carry a combination rationale.
  • If the relationship were real and ran the other way, AKT-driven signalling could buffer a menin inhibitor's effect, which would show up as intrinsic resistance nobody had a candidate mechanism for. That is a reason to measure AKT signalling under menin inhibition, not a reason to believe this row.
Still open
  1. What is the wild-type AKT1 BRET value against MEN1 in Table S2(A)? 'Mutation causing' implies wild type is at background, and the number that says so has never been quoted here.
  2. Is MEN1 a labelled node in Figure 4F, the AKT1 E17K spoke diagram? It was not identifiable at the resolution read, which would mean the authors did not carry menin into their own AKT1 validation set.
  3. Does a menin inhibitor change AKT signalling in a KMT2A-rearranged line? This is answerable from existing deposited RNA-seq and phospho-proteomic data and would bear on the question far more directly than the IntAct row does.
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-63961482 (bret, HEK293T) curate a MEN1-AKT1 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 AKT1, Venus acceptor on MEN1). The AKT1 side carries feature(s) P31749:p.Glu17Lys, typed by IntAct as 'mutation causing'. The row is annotated to Table S2(B), primary screen CARINA output 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 P31749 (AKT1) is 480 aa. Subcellular location: Cytoplasm (ECO:0000250), Nucleus (ECO:0000269), Cell membrane (ECO:0000269), Mitochondrion intermembrane space (ECO:0000250). Tissue specificity: Expressed in all human cell types so far analyzed 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
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