How menin silences JunD: pocket binding plus uncoupling from MAP kinase signalling
also called menin JunD repression · menin AP-1 repression · JunD phosphorylation block
Menin holds JunD in a groove and stops the cell's growth signals from switching it on, so the gene programmes JunD drives stay quiet. Two separate blocks are involved, one for each of the main growth-signal pathways.
The same thing, for a scientist
Menin represses JunD by two linked mechanisms. First, direct binding: menin binds a short JunD peptide in its single deep pocket and represses JunD-mediated transcriptional activation from both Gal4-fusion and AP-1-responsive reporters [E1]. Second, signal uncoupling: menin inhibits ERK-dependent phosphorylation and activation of JunD and of Elk-1, inhibits JNK-mediated phosphorylation of JunD and c-Jun, and represses inducible c-fos promoter activity - acting **downstream of MAPK activation**, since it does not interfere with activation of ERK2 or JNK1 themselves [E2]. An N-terminal menin deletion mutant that cannot block JNK-mediated JunD phosphorylation still represses ERK2-mediated phosphorylation, which separates the two into distinct inhibitory mechanisms [E2]. The net effect is that menin prevents accumulation of active Fos/Jun heterodimers, which is the molecular statement of its tumour-suppressor role [E2]. Crucially for the drug question, only the first mechanism is obviously pocket-dependent.
Two mechanisms, and only one of them is a drug target
| Mechanism | What menin does | Pocket-dependent? |
|---|---|---|
| Direct binding and transcriptional repression | binds JunD peptide in the deep pocket; represses JunD-driven reporters 13 | Yes - this is the site a menin inhibitor occupies |
| Uncoupling from ERK | blocks ERK-dependent phosphorylation of JunD and Elk-1, downstream of ERK2 activation 2 | Not established; survives N-terminal deletion |
| Uncoupling from JNK | blocks JNK-mediated phosphorylation of JunD and c-Jun 2 | Not established; lost with N-terminal deletion |
This distinction matters more than it has been given credit for in this project. A pocket ligand removes menin from the JunD peptide. It does not obviously remove menin from the cell, and menin's other repressive activities - including whichever of the kinase-uncoupling effects are not pocket-mediated - could persist. That is a mechanistic reason why pharmacological occupancy might be less consequential than MEN1 mutation, and it should be stated as such.
The opposite consideration also holds. If menin-inhibitor treatment leads to menin degradation, as has been proposed in this graph's resistance entries, then all menin functions are lost, not only the pocket-mediated one, and the distinction collapses. Which of these applies in an endocrine cell on drug is unmeasured.
Where this was shown, and where it was not
Every experiment above was done in HeLa cells or immortalised fibroblasts with overexpressed constructs 12. None was done in parathyroid, islet or pituitary tissue, at endogenous expression, or with a small molecule. The structural work that localises the interaction to the shared pocket used purified protein and peptides 3.
So the chain is: structure is solid, cell biology is solid but in the wrong cell type, and the pharmacology is absent. The missing link between this mechanism entry and any clinical claim was a single experiment - does a clinical menin inhibitor release JunD from menin in a cell? That experiment has now been reported and this entry's absence claim is withdrawn. PMID 42371796 (Blood, 2026) used quantitative mass spectrometry in MLLr leukaemic cells to show that menin-MLL inhibitors disrupt menin-JUND interactions, and its own abstract records that before it "the impact of menin-MLL inhibitors on JUND function has remained unexplored" - so the claim was true when written and is not now.
Withdrawn: the pharmacology is no longer absent, and it points the opposite way
This entry said the pharmacological link was missing. It is not, and the result is more interesting than the experiment it was waiting for.
PMID 42371796 (Ozyerli-Goknar et al., Blood, 2026; authors include Armstrong SA and McGeehan GM of Syndax, revumenib's maker):
- Quantitative mass spectrometry in MLLr leukaemic cells shows menin-MLL inhibitors disrupt menin-JUND interactions, as this entry's structural argument predicted.
- But menin-inhibitor treatment increases JUND chromatin occupancy, upregulating JUND target genes and contributing to tumorigenesis and therapy resistance.
- CRISPR inactivation of JUND, or JNK inhibition, synergises with menin-MLL inhibitors - reduced proliferation, cell cycle arrest, apoptosis.
The direction matters. This entry framed menin-JunD as repression that a drug would relieve, with the therapeutic question left open. The measured answer is that relieving it helps the leukaemia: displacing JunD from menin frees it onto chromatin, and that is a resistance route rather than a bonus. A JNK inhibitor combination is the countermeasure the paper proposes.
How this was found, and why it is a process failure. The graph already cited this paper in ten other entries, including gene-jund and exp-jund-displacement-coip-under-clinical-menin-inhibitor. It did not propagate here, and a PMID-keyed sweep could never have found it, because this entry does not cite the paper - it asserts the absence the paper fills. Standing rule 45 covers correcting entries that share a citation; this is the other direction, and it is what the stale-absence queue exists to catch. That queue had been deferred for four cycles.
| repressor | gene-men1 |
|---|---|
| target | gene-jund |
| net effect | prevents accumulation of active Fos/Jun heterodimers |
| endocrine tissue tested | false |
| small molecule tested | false |
| critical missing experiment | co-immunoprecipitation of menin and JunD in an endocrine cell line under revumenib, ziftomenib or bleximenib at clinical concentrations |
mechanisms
[
{
"name": "direct pocket binding and transcriptional repression",
"pocket_dependent": true,
"evidence": "E1, E3"
},
{
"name": "uncoupling of JunD from ERK-dependent phosphorylation",
"pocket_dependent": "not established",
"evidence": "E2"
},
{
"name": "uncoupling of JunD and c-Jun from JNK-mediated phosphorylation",
"pocket_dependent": "not established",
"evidence": "E2"
}
]cell systems used
[ "HeLa", "immortalised fibroblasts" ]
- This mechanism entry contains the best argument against its own beat: menin represses JunD by at least two routes and only one is clearly pocket-mediated, so a competitive inhibitor may reproduce only part of the MEN1 phenotype.
- All of the cell biology is in HeLa cells and fibroblasts with overexpressed protein. None of it is in an endocrine cell, at endogenous levels, or with a drug.
- If a clinical menin inhibitor turns out not to release JunD in cells, the endocrine liability argument has no mechanism left and should be withdrawn.
- Is the JUND release class-wide or revumenib-specific? The abstract names revumenib; ziftomenib and bleximenib occupy the same pocket and would be predicted to do the same, and if they do not, that is a selectivity handle.
- Does JUND chromatin occupancy rise in patients on menin inhibitors, and does it track resistance? The trial samples exist and this is a CUT&RUN on banked material.
- Which of menin's three repressive activities on JunD survive pocket occupancy by a clinical inhibitor? If the kinase-uncoupling arms survive, pharmacological inhibition is a strictly weaker perturbation than MEN1 mutation.
- Does menin-inhibitor treatment reduce menin protein levels in endocrine tissue? If it does, the pocket-versus-whole-protein distinction disappears.
- What are the JunD target genes in parathyroid chief cells, islet beta cells and pituitary lactotrophs? Without a tissue-specific target list there is no readout for whether repression has been relieved in the tissues that matter.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Menin binds JunD directly and represses JunD-mediated transcriptional activation from both a Gal4-responsive reporter and an AP-1-responsive reporter; menin did not bind other Jun or Fos family members directly, and several naturally occurring clustered MEN1 missense mutations disrupted the menin-JunD interaction.
Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription · Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY, Saggar S, Chandrasekharappa SC, Collins FS, Spiegel AM, Marx SJ, Burns AL · Cell 96:143-52 1999What this evidence cannot show
Read as abstract. Yeast two-hybrid discovery with in vitro and in vivo confirmation, and reporter assays in HeLa cells with overexpressed constructs. Not endocrine tissue, not endogenous expression.
Evidence that argues against this (1)
- Both readouts are artificial promoters - a Gal4-responsive reporter and an AP-1-responsive reporter - and repression of a transfected reporter is not repression of endogenous JunD target genes in their native chromatin. The entry states a mechanism from reporter data alone. Cell 1999
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Menin inhibits ERK-dependent phosphorylation and activation of JunD and Elk-1, inhibits JNK-mediated phosphorylation of JunD and c-Jun, and represses inducible c-fos promoter activity, acting downstream of MAPK activation since it does not interfere with ERK2 or JNK1 activation; an N-terminal menin deletion mutant that cannot inhibit JNK-mediated JunD phosphorylation still represses ERK2-mediated phosphorylation, indicating two distinct inhibitory mechanisms, with the net effect of inhibiting accumulation of active Fos/Jun heterodimers.
Menin uncouples Elk-1, JunD and c-Jun phosphorylation from MAP kinase activation · Gallo A, Cuozzo C, Esposito I, Maggiolini M, Bonofiglio D, Vivacqua A, Garramone M, Weiss C, Bohmann D, Musti AM · Oncogene 21:6434-45 2002What this evidence cannot show
Read as abstract. HeLa cells with menin overexpression; the two-mechanism conclusion rests on a single N-terminal deletion mutant, and the abstract does not map either mechanism onto the peptide-binding pocket. Whether either survives pharmacological pocket occupancy is untested.
Evidence that argues against this (1)
- If the kinase-uncoupling arms of menin's repression of JunD are not pocket-mediated, then a competitive pocket ligand would reproduce only part of what a MEN1 loss-of-function mutation does. That is a substantive argument that pharmacological menin inhibition is a weaker perturbation than the genetic one, and it follows from this same paper's separation of the mechanisms. Gallo A et al. 2002
- E3established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
Human menin contains a single deep peptide-binding pocket that binds short MLL1 and JUND peptides in the same manner with opposite transcriptional effects; menin-JUND blocks JNK-mediated JUND phosphorylation and suppresses JUND-induced transcription while menin-MLL1 promotes transcription.
The same pocket in menin binds both MLL and JUND but has opposite effects on transcription · Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X, Lei M · Nature 482:542-6 2012What this evidence cannot show
Read as abstract. Structural and cell-based work with no menin inhibitor and no endocrine tissue.
Evidence that argues against this (1)
- A single deep pocket binding both peptides 'in the same manner' is a structural statement about binding mode. It does not follow that displacing one displaces the other proportionally in a cell, where local concentration, chromatin tethering and competing partners all bear on occupancy and none was measured. Nature 2012
- E-pharmstrong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.journal-article
Menin-MLL inhibitors disrupt the menin-JUND interaction in MLL-rearranged leukaemic cells, shown by quantitative mass spectrometry, and treatment increases JUND chromatin occupancy and target-gene expression in a way that contributes to tumorigenesis and therapy resistance. CRISPR inactivation of JUND or JNK inhibition synergises with menin-MLL inhibitors.
Menin-MLL inhibitors enhance JUND activity in MLLr leukemic cells contributing to tumorigenesis and therapy resistance · Ozyerli-Goknar E, Nizamuddin S, Fetsch V, et al. · Blood 2026What this evidence cannot show
Read from the abstract 2026-09-20; the paper is online ahead of print (blood.2025032363) and the full text has not been retrieved here, so the cell lines, inhibitor concentrations and whether the effect is revumenib-specific or class-wide are not established from this reading. The abstract names **revumenib** as the clinical agent. Syndax, revumenib's manufacturer, is represented in the author list, which cuts both ways - access to the compound, and an interest in the combination it proposes.
Evidence that argues against this (2)
- The synergy claim is the part most in need of independent replication. A CRISPR knockout and a JNK inhibitor are very different perturbations, and JNK inhibitors are notoriously non-selective; synergy with a pan-JNK inhibitor is weak evidence that JUND is the node. The mass-spectrometry displacement result is the solid part. Ozyerli-Goknar E et al. 2026
- This entry's original structural argument survives intact and is not affected: menin binds JunD through the MLL1/2 binding pocket, so a pocket inhibitor displacing JunD was always the prediction. What was wrong was the assumption that displacement would be therapeutically neutral or favourable. Oncofusion knowledge graph (internal analysis) 2026
menin represses JunD by pocket binding and by uncoupling it from ERK and JNK phosphorylation
only the direct-binding arm of the repression is clearly pocket-mediated, which is the arm a drug removes
- ← depends onReleasing JunD does not merely de-repress it: JunD without menin becomes a growth promoter
what happens after the repression described there is lifted
its absence claim is stale: PMID 42371796 reports the menin-inhibitor experiment it said had not been done
same corepressor-recruitment architecture; different site, and NF-kB is not known to use the MBM pocket