PKA phosphorylates menin at Ser487 and pulls it off chromatin - a kinase input on the drug target itself
also called menin S487 · GLP-1 menin phosphorylation · PKA menin
Menin is the protein that menin inhibitors aim at. A hormone signal acting through the enzyme PKA puts a phosphate on menin at one spot, and phosphorylated menin gets pulled away from DNA by the cell's skeleton proteins. Something other than a drug can already move menin off the genes it sits on.
The same thing, for a scientist
GLP-1 signalling activates PKA, which **directly phosphorylates menin at Ser487**. Phospho-S487 menin gains binding affinity for **nuclear actin/myosin IIa** and is **sequestered from the Ins1 promoter**, reducing recruitment of SUV39H1 and HDAC1 and de-repressing transcription; it also increases cyclin D2 expression and beta-cell proliferation. S487 is independently observed as a phosphosite on MEN1 (O00255) in PRIDE re-analysis - one of only four. **The interest for this beat is not beta cells.** It is that the therapeutic target of revumenib and ziftomenib carries a kinase-controlled switch that moves it off chromatin, in a direction that phenocopies what a menin inhibitor is supposed to do, through a completely different mechanism. **Nobody has asked what PKA activation does to a KMT2A-rearranged cell.**
The switch, as reported in beta cells
- GLP-1 receptor signalling raises cAMP and activates PKA.
- PKA phosphorylates menin at S487.
- Phospho-S487 menin binds nuclear actin and myosin IIa more strongly.
- Menin is sequestered away from the Ins1 promoter.
- SUV39H1 and HDAC1 recruitment falls; Ins1 transcription rises.
- Cyclin D2 rises; beta cells proliferate 1.
Every step is in pancreatic beta cells. None of it has been tested in a leukaemic cell.
Why a leukaemia beat should care
Menin inhibitors work by blocking the pocket that receives the KMT2A MBM1 motif, releasing the fusion from chromatin. This mechanism releases menin from chromatin by a different route - a post-translational modification that changes what menin prefers to bind.
Three questions follow, none of them asked in the literature this beat searched:
- Does PKA activation displace menin, and with it the KMT2A fusion, from HOXA/MEIS1 loci?
- Is basal S487 occupancy a covariate of menin-inhibitor response? A menin already partly sequestered is a smaller pool for the drug to act on, and could read as either sensitivity or resistance.
- Do menin-inhibitor resistance mutations in MEN1 alter S487 or its context? The graph carries
resistance-men1-interface-mutations; whether any of them sit near residue 487 is checkable.
The endocrine literature and the leukaemia literature are not talking to each other here, and this graph already carries an endocrine beat that could close the gap.
| kinase | PKA (protein kinase A, cAMP-dependent) |
|---|---|
| substrate | gene-men1 |
| uniprot | O00255 |
| site | S487 |
| gated contact | nuclear actin / myosin IIa binding, causing sequestration from chromatin |
| system | pancreatic beta cells; GLP-1 signalling |
| tested in leukaemia | false |
| fate in fusion | not applicable - menin is a partner, not part of the fusion chain |
| observed in proteomics | true |
- Any attempt to exploit this in leukaemia collides with the endocrine axis the graph already flags: menin is a tumour suppressor in endocrine tissue and this exact mechanism drives beta-cell proliferation. A drug that pushed menin off chromatin systemically would be doing in the pancreas what MEN1 loss does.
- If phospho-S487 sequesters menin, a patient on a GLP-1 receptor agonist may have a smaller chromatin-bound menin pool, which could reduce the target available to a menin inhibitor or could mimic part of its effect. Both directions are plausible and neither is measured - this is an untested drug-drug interaction in a population where GLP-1 agonist use is high.
- The whole mechanism is from one beta-cell paper. Building a leukaemia intervention on it without a haematopoietic replication would repeat a pattern this project has criticised elsewhere.
- Does PKA activation - forskolin, or a GLP-1 receptor agonist - displace menin and the KMT2A fusion from HOXA9/MEIS1 in a t(4;11) or t(9;11) line? A single ChIP experiment.
- Is basal phospho-S487 a covariate of menin-inhibitor sensitivity across cell lines? The reagents exist and the hypothesis is directional.
- Do any reported MEN1 resistance mutations lie near residue 487 or alter the PKA consensus around it?
- GLP-1 receptor agonists are among the most widely prescribed drugs in the world. Has anyone looked at menin-inhibitor pharmacodynamics in patients on one?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
GLP-1-signalling-activated protein kinase A directly phosphorylates menin at serine 487; Ser487-phosphorylated menin gains binding affinity for nuclear actin and myosin IIa and is sequestered from the Ins1 promoter, reducing recruitment of SUV39H1 and HDAC1, increasing Ins1 transcription, cyclin D2 expression and beta-cell proliferation.
GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells. · Xing B, et al. · J Cell Biol 2019What this evidence cannot show
Abstract read 2026-09-19; full text available as PMC6400573 but not read in this session. Entirely a pancreatic beta-cell system - mouse and cell line - with no haematopoietic data and no KMT2A fusion present. Whether S487 phosphorylation affects the menin-MBM1 interaction at all is not addressed.
Evidence that argues against this (1)
- Menin's role is cell-type-specific to the point of reversal: in the same menin pocket, MLL and JUND binding have opposite transcriptional effects, and menin is a tumour suppressor in endocrine tissue while behaving as a required cofactor in KMT2A-rearranged leukaemia. A regulatory switch characterised in beta cells cannot be assumed to run the same way, or at all, in a leukaemic blast. Huang J et al. 2012
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database
MEN1 Ser487 is one of only four phosphorylation sites observed on menin (O00255) in the PRIDE/PTMeXchange re-analysis served by the EMBL-EBI Proteins API, the others being S543, S593 and T594; a scan of the full menin sequence for canonical 14-3-3 binding modes returns zero matches.
Proteins API proteomics-PTM, O00255 (MEN1_HUMAN): 10 modified residues, 4 phosphorylation sites · EMBL-EBI 2026What this evidence cannot show
Fetched 2026-09-19. Four observed sites on a 610-residue protein is sparse and may reflect low sampling rather than low modification; menin is far less abundant than the proteins that dominate shotgun runs. The absence of canonical 14-3-3 motifs on menin was checked because the sequestration partner here is actin/myosin, not 14-3-3, and the two mechanisms should not be conflated.
Evidence that argues against this (1)
- Four observed sites is close enough to the detection floor that the set cannot be treated as a census: UniProt's own curated table for the same protein carries sites the proteomics set does not, the same non-nesting relationship documented for KMT2A. A phosphosite-poor appearance here is at least partly an artefact of protein abundance. UniProt Consortium 2026
PKA phosphorylation at S487 sequesters menin from chromatin
a kinase route to the same endpoint a menin inhibitor produces, untested in leukaemia
modifies the availability of the protein that presents this pocket
- ← related toDNA damage raises menin levels through ATM/ATR phosphorylation, and the residue has never been mapped
the opposite-direction kinase input on the same target
Ser487 lies eight residues C-terminal to NLS-1, inside the same disordered region