A second brake, unconnected to JunD: menin is a TEAD1 corepressor with VGLL4 in the beta cell
also called MENIN TEAD1 VGLL4 · Hippo pathway menin beta cell · menin FZD7 CCN2
Menin does not only work through JunD. In insulin-making cells it also teams up with a protein called VGLL4 to switch off a growth programme run by TEAD1. That is a second, separate way menin holds the cell still.
The same thing, for a scientist
Beta-cell-specific TEAD1 deletion increases beta-cell proliferation cell-autonomously, while deletion of the canonical TEAD coactivators YAP and TAZ does not - implying repressive cofactors. A split-GFP and yeast two-hybrid screen identified VGLL4 and MENIN as TEAD1 corepressors in beta cells; both bind TEAD1 and repress target genes including FZD7 and CCN2, and that repression inhibits beta-cell proliferation. The authors propose targeting them to augment beta-cell proliferation for diabetes [E1]. This matters structurally for the endocrine-liability argument: menin's restraint of the beta cell runs through **at least two independent partners** - JunD and TEAD1 - and it is not established that a pocket-directed inhibitor engages both equally.
Why a second brake changes the pharmacology question
interface-menin-jund-pocket treats the endocrine liability as a single-pocket problem: drug occupies the MBM1 site, JunD is displaced, endocrine restraint is lost. If menin restrains the beta cell through TEAD1 as well, then either (a) the TEAD1 interaction also uses the central pocket, in which case the liability is broader than the JunD story implies, or (b) it does not, in which case a menin inhibitor removes only part of the restraint and the endocrine consequences are correspondingly partial. Neither has been tested, and the answer moves the risk estimate in opposite directions. It is a cheap structural question: does the TEAD1 interaction survive a clinical menin inhibitor?
What was actually shown
- Beta-cell-specific TEAD1 deletion increases beta-cell proliferation, cell-autonomously 1.
- Beta-cell-specific YAP/TAZ deletion does not affect proliferation, so the canonical coactivator arm is not what TEAD1 is doing here 1.
- An improved split-GFP system plus yeast two-hybrid identified VGLL4 and MENIN as TEAD1 corepressors in beta cells 1.
- Both bind TEAD1 and repress FZD7 and CCN2; that repression inhibits beta-cell proliferation 1.
| partner | TEAD1 |
|---|---|
| cofactor | VGLL4 |
| tissue | pancreatic beta cell |
| interface mapped | false |
| tested against menin inhibitor | false |
targets
[ "FZD7", "CCN2" ]
- If TEAD1 corepression is pocket-dependent, the endocrine liability of a menin inhibitor is broader than the JunD-only account in this graph and includes a Hippo-pathway arm nobody has looked at.
- FZD7 and CCN2 de-repression is a WNT and a matricellular growth programme respectively, neither of which is benign in a growing child.
- A partial phenotype is not a safe phenotype; it is an unmeasured one.
- Does the menin-TEAD1 interaction use the central peptide pocket that revumenib occupies? A competition experiment with a clinical compound would answer it in a week.
- If menin restrains the beta cell through two independent partners, does a pocket inhibitor produce a partial phenotype, and is that why the in-vivo drug phenotype is compensatory proliferation rather than neoplasia?
- Is VGLL4 expression a modifier of who gets an endocrine effect on a menin inhibitor?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
MENIN and VGLL4 act as TEAD1 corepressors in beta cells, repressing FZD7 and CCN2 and inhibiting proliferation.
VGLL4 and MENIN function as TEAD1 corepressors to block pancreatic beta cell proliferation. · Li F, Liu R, Negi V, Yang P, Lee J, Jagannathan R, et al. · Cell Reports 2023What this evidence cannot show
Mouse genetics plus interaction screens; the menin-TEAD1 interaction surface is not mapped and no inhibitor was tested against it; FZD7/CCN2 are shown as targets but the proliferative contribution of each is not separated.
Evidence that argues against this (1)
- The best-characterised menin restraint in this tissue runs through JunD and the central peptide pocket, which is what clinical inhibitors occupy; if TEAD1 binding uses a different surface, this mechanism may be entirely untouched by the drug and irrelevant to the clinical question. Ma J et al. 2021
Menin restrains the beta cell through at least two independent partners (JunD and TEAD1); the single-pocket account of endocrine liability is incomplete, and whether the TEAD1 surface is drug-occupiable is untested
MENIN acts as a TEAD1 corepressor with VGLL4, repressing FZD7 and CCN2 in beta cells