Oncofusion

start / graph / interface-menin-pten-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Interfaceweak confidence 2 of 5: Preliminary, small, indirect, or not yet peer reviewed.Q128-the-menin-interactome-that-is-not-chromatin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-PTEN is ONE BRET well from the extended-driver arm, for R173C only - declined

also called menin-PTEN · PTEN R173C neoPPI · EBI-63958506

A database lists the tumour suppressor PTEN as a menin partner. It rests on one well in an automated screen, testing the mutant PTEN R173C rather than the normal protein.

The same thing, for a scientist

**Verdict: DECLINED.** IntAct record EBI-63958506 is the whole evidence base: one BRET measurement, PMID 35512704, HEK293T, NanoLuc-PTEN R173C donor and Venus-MEN1 acceptor, type 'proximity', annotated to **Table S6** (the extended-driver arm), intact-miscore **0.27** [E1]. The PTEN feature is `P60484:p.Arg173Cys`, typed **`mutation causing an interaction`** [E1] - which resolves to substitution level the allele cycle 72 could only place at residue 173, and does so from the REST feature string rather than from recall. Menin appears nowhere in the paper's prose [E2]. **Compartment does not argue against this pair either**: UniProt gives PTEN experimentally coded Cytoplasm, Nucleus and Nucleus/PML body [E3]. So, as with AKT1, the decline is purely about assay thinness and allele-dependence. **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
EBI-63958506   MEN1 (Venus, acceptor)  <->  PTEN (NanoLuc, donor)
  detectionMethod  bret
  type             proximity
  host             Homo sapiens HEK293T embryonic kidney cell
  featureShortLabelsB  ['P60484:p.Arg173Cys', 'nluc tag']
  featureTypesB        ['mutation causing', 'nluc']
  annotations          ['figure legend (ST6)']
  intactMiscore    0.27

One well, one table, one publication. No pull-down, no co-IP, no NanoPCA, no mapped region on either protein, no stoichiometry (IntAct records 0-0 on both sides, meaning not determined).

R173C is a destabilising allele, which is a specific reason for caution

PTEN R173 sits in the C2 domain. Substitutions there are among the classic Cowden-syndrome and somatic PTEN missense lesions and are associated with reduced protein stability and mislocalisation rather than with a clean catalytic-dead phenotype.

This matters for a proximity assay specifically. A destabilised, partly misfolded, over-expressed protein is more likely to enter chaperone and quality-control interactions and to populate non-native compartments than its wild-type counterpart. A BRET gain for a destabilising missense allele against an abundant nuclear protein therefore has an obvious non-specific explanation that the single assay cannot exclude. That is an argument for reading the wild-type value in Table S6(A) rather than for writing the row down.

The same reasoning applies, with less force, to SMAD4 R361 and to the FBXW7 arginine substitutions, and it is one candidate explanation for why so many of this screen's menin rows are missense hotspots in structurally sensitive positions.

Facts and figures
partner agene-men1
partner bPTEN
partner b uniprotP60484
partner b length AA403
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.
alleleP60484:p.Arg173Cys
n methods1
intact miscore0.27
source panelTable S6, extended-driver arm of the primary screen
closesthe residue-only PTEN entry in ana-menin-neoppi-trap-ten-intact-partners-from-one-mutation-screen; the substitution is R173C
absence classmeasured-not-reported
absence class noteWild-type PTEN versus R173C BRET against MEN1 was measured and is in Mo et al. Table S6(A) inside PMC9597701; unread here. Whether endogenous menin and endogenous PTEN ever meet is a separate, never-measured question.
interface residues a
[]
structures
[]
ligands
[
  "drug-revumenib",
  "drug-ziftomenib"
]
records
[
  "EBI-63958506 (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
  • PTEN-null disease is the population where a PI3K/AKT-axis combination with a menin inhibitor would be proposed, and this row would be cited as mechanistic support. It cannot bear that weight: it is one well testing a PTEN protein that is present, not absent.
  • PTEN loss and menin inhibition could interact clinically for reasons that have nothing to do with a physical complex - shared downstream transcriptional programmes, for example. Declining the complex must not be allowed to close the clinical question.
Still open
  1. What is the wild-type PTEN BRET value against MEN1 in Table S6(A)?
  2. Do destabilising missense alleles as a class show inflated BRET against abundant nuclear acceptors in this dataset? That is answerable from Table S2(A) alone and would be a general quality control on every neoPPI row in IntAct, not just menin's.
  3. PTEN loss is a recurrent event in T-lineage acute leukaemia, including some KMT2A-rearranged T-ALL. Does PTEN status modify menin-inhibitor response? That question is worth asking on its own merits and does not depend on this row being real.
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-63958506 (bret, HEK293T) curate a MEN1-PTEN 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 PTEN, Venus acceptor on MEN1). The PTEN side carries feature(s) P60484:p.Arg173Cys, 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 P60484 (PTEN) is 403 aa. Subcellular location: Cytoplasm (ECO:0000269), Nucleus (ECO:0000269), Nucleus PML body (ECO:0000269), plus a Secreted line (ECO:0000269). Tissue specificity: Expressed at a relatively high level in all adult tissues 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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