PBX proteins are not constitutively nuclear: a MEINOX partner keeps them there by blocking export - and nobody has ever looked at PBX3 in a KMT2A-rearranged cell
also called PBX nuclear import/export · PREP1-PBX1 nuclear retention · TALE cofactor subcellular localization
A transcription factor only works inside the nucleus, and PBX proteins carry signals both for going in and for coming out, so it is their partner protein binding them that keeps them in. If that holds for PBX3 and MEIS1 in leukemia cells then breaking the pair would move one of them out of the nucleus altogether - and nobody has ever checked.
The same thing, for a scientist
PBC-class TALE proteins carry both nuclear localisation and nuclear export signals, and their subcellular distribution is regionally restricted in development rather than constitutively nuclear. MEINOX-class partners - PREP1 in mammals, Homothorax in *Drosophila* - are themselves cytoplasmic and require association with PBX/EXD to reach the nucleus; co-expression drives nuclear localisation of the heterodimers in cell contexts where PBX alone is exported, and the proposed mechanism is **blocking nuclear export rather than adding an import signal** [E1]. A second, partner-independent determinant exists: non-muscle myosin promotes cytoplasmic localisation of PBX [E2]. **Neither has ever been examined for PBX3 with MEIS1 in a haematopoietic cell, let alone a KMT2A-rearranged one** - a gap this entry records rather than fills. Its relevance is that it would add a fourth, separable function to the MEIS1-PBX3 interface, alongside MEIS1 protein stabilisation, ternary DNA binding and transcriptional reinforcement (`mechanism-pbx3-meis1-dimer-transforms-without-hoxa9`).
What was measured, and in what
Berthelsen et al. studied EXD, PBX, HTH and PREP1 in several cell contexts 1:
- HTH and PREP1 are cytoplasmic on their own and require association with EXD/PBX for nuclear localisation.
- EXD and PBX1 are nuclear in murine fibroblasts but NOT in Drosophila Schneider cells, where they are actively exported to the cytoplasm. So PBX's own localisation is cell-context-dependent, not a fixed property.
- Co-expression of EXD/PBX with HTH/PREP1 produces nuclear localisation of the heterodimers in both contexts.
- The authors propose that heterodimerisation induces nuclear translocation by blocking nuclear export.
The systems are murine fibroblasts and Drosophila Schneider cells. This is developmental cell biology, and it is the entirety of what the field has established about how a PBC protein gets and stays into a nucleus.
The second determinant, which is partner-independent
Localisation is not only about the MEINOX partner. Non-muscle myosin promotes cytoplasmic localisation of PBX 2.
That matters here for a specific reason: it means a cell can hold PBX out of the nucleus without changing its partner, and conversely that disrupting a MEIS-PBX interface might not relocalise PBX3 at all if the myosin route dominates. Any prediction that an interface inhibitor will mislocalise PBX3 has to survive this, and the entry records it as the most likely way the prediction fails rather than burying it.
The gap, stated as a gap
No source read this cycle reports:
- PBX3 subcellular distribution in any haematopoietic cell;
- PBX3 subcellular distribution in any KMT2A-rearranged cell, of any lineage or species;
- whether MEIS1 controls PBX3 nuclear retention as PREP1 controls PBX1's;
- any subnuclear localisation - speckles, condensates, chromatin fractions - for PBX3 or MEIS1 in this disease.
This is written as an unchecked gap, not as a counted absence. A systematic query of the form PBX3 AND (nuclear localization OR subcellular) was NOT run this cycle, so the honest status is that the beat did not find such a measurement while reading around the interface, which is weaker than a bounded zero and is labelled as such. Brief rule 67 forbids reporting an unrun query as an absence, and this is the compliant form of not knowing.
Why it is worth someone's week. Subcellular and subnuclear localisation is a standing PI priority and most entries in this area are thin on it. A fractionation blot plus immunofluorescence for PBX3 and MEIS1 in SEM and RS4;11, with and without PBX3 or MEIS1 knockdown, would answer all four bullets at once and is a week of standard work with commercial antibodies.
| mechanism class | nucleocytoplasmic transport control of a transcription factor by heterodimerisation |
|---|---|
| compartment | nucleus, conditionally; cytoplasm when the partner is absent or when the myosin route dominates |
| proposed mechanism | MEINOX-class heterodimerisation BLOCKS the PBC protein's nuclear export signal rather than supplying an import signal |
| partner independent determinant | non-muscle myosin promotes cytoplasmic localisation of PBX (PMID 12724421, read at title level) |
| nls nes coordinates | NOT asserted - the signal sequences and their residue positions were not read from the full text, and a guessed coordinate is worse than an omission |
| subnuclear localization | no data located for PBX3 or MEIS1 in this disease - no speckle, condensate or chromatin-fraction measurement |
| gap status | UNCHECKED, not a counted absence. No systematic query of the form PBX3 AND (nuclear localization OR subcellular) was run this cycle; the beat simply did not encounter such a measurement while reading the interface literature. Rule 67 forbids presenting an unrun query as a zero. |
| decisive cheap experiment | nuclear/cytoplasmic fractionation blot plus immunofluorescence for PBX3 and MEIS1 in SEM and RS4;11, with and without PBX3 or MEIS1 knockdown; commercial antibodies, about one week |
established for
{
"PBC_protein": "PBX1 and Drosophila EXD",
"MEINOX_partner": "PREP1 and Homothorax",
"cells": "murine fibroblasts; Drosophila Schneider cells"
}NOT established for
{
"PBC_protein": "PBX3",
"MEINOX_partner": "MEIS1",
"cells": "any haematopoietic cell; any KMT2A-rearranged cell of any lineage or species"
}- This entry's own evidence is a 1999 fly-and-fibroblast paper and a 2003 title. Anything built on it should be treated as a prediction about PBX3/MEIS1, not a fact about them, and the entry says so in its data block rather than only in prose.
- If an interface inhibitor did mislocalise PBX3, it would do so in normal haematopoietic and developing cells too - localisation control is developmental machinery, and the patients are infants.
- The partner-independent myosin route [E2] is the most likely way a relocalisation prediction fails, and it would fail silently: an agent could disrupt the interface perfectly and leave PBX3 exactly where it was.
- Recording a gap is not the same as filling it. The graph gains a labelled hole here and a one-week experiment; it does not gain a localisation fact, and this entry should not be cited as though it does.
- Where is PBX3 in a KMT2A::AFF1 blast? Nuclear, cytoplasmic, or partitioned - and does the partition move when MEIS1 is knocked down? Nobody has looked, in any lineage.
- Does MEIS1 do for PBX3 what PREP1 does for PBX1? If so, the MEIS1-PBX3 interface acquires a fourth separable function and becomes a materially better target.
- Is there any subnuclear structure - speckle, condensate, chromatin compartment - that PBX3 or MEIS1 occupies in this disease? This graph carries subnuclear entries for polycomb bodies and the lamina and has none for the TALE factors.
- Does the non-muscle myosin route operate in haematopoietic cells? If it dominates, then partner-based relocalisation is not achievable and one of the arguments for targeting the interface falls away.
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Nuclear localisation of the Extradenticle (EXD) and PBX1 proteins is regionally restricted during Drosophila and mammalian development; HTH and PREP1 are cytoplasmic and require association with EXD/PBX for nuclear localisation; EXD and PBX1 are nuclear in murine fibroblasts but are actively exported to the cytoplasm in Drosophila Schneider cells; and co-expression of EXD/PBX with HTH/PREP1 causes nuclear localisation of their heterodimers in both cell contexts, which the authors propose works by blocking their nuclear export.
The subcellular localization of PBX1 and EXD proteins depends on nuclear import and export signals and is modulated by association with PREP1 and HTH · Berthelsen J, Kilstrup-Nielsen C, Blasi F, Mavilio F, Zappavigna V · Genes & Development 13:946-953 1999What this evidence cannot show
Abstract read this cycle; full text not retrieved, so the actual NLS and NES sequences and residue positions are NOT asserted anywhere in this entry. The proteins are PBX1 and Drosophila EXD with PREP1 and HTH - NOT PBX3 and NOT MEIS1 - and the cells are murine fibroblasts and Drosophila Schneider cells, neither haematopoietic. The result is also 1999 and rests on overexpression and immunofluorescence, which for a nuclear/cytoplasmic partition is an appropriate method but an insensitive one. Rule 73: the system is named in the claim because it is nothing like the index disease.
Evidence that argues against this (1)
- PBX localisation has at least one determinant that does not involve a MEINOX partner at all - non-muscle myosin promotes cytoplasmic localisation of PBX - so a partner-based model of PBX nuclear retention is incomplete even within the family it was established in. Huang H et al. 2003
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Non-muscle myosin promotes cytoplasmic localisation of PBX, establishing a determinant of PBX subcellular distribution that is independent of MEINOX-class partner binding.
Nonmuscle myosin promotes cytoplasmic localization of PBX · Huang H, Paliouras M, Rambaldi I, Lasko P, Featherstone M · Molecular and Cellular Biology 23:3636-3645 2003What this evidence cannot show
The claim is taken from the paper's TITLE and its bibliographic record, fetched from PubMed on 2026-09-20; the abstract was not read. Graded moderate for that reason, and it should not be quoted for anything beyond the existence of a myosin-dependent cytoplasmic route. Which PBX paralogue, which cell type and which myosin are all unknown from what was read.
Evidence that argues against this (1)
- A claim read at title level is the weakest citation form this graph permits; it is recorded so that a later reader knows this determinant exists to be checked, not so that it can be built on. Huang H et al. 2003
- E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
In murine Hoxa9-transformed cells, the Pbx3-Meis1 interface already carries three separable functions - preventing Meis1 ubiquitination, permitting high-affinity ternary DNA/Hoxa9/Meis1/Pbx3 complex formation, and transcriptional induction of endogenous Meis1 by Pbx3 - which is why a fourth, localisation function would materially change the target profile of that interface.
Pbx3 and Meis1 cooperate through multiple mechanisms to support Hox-induced murine leukemia · Garcia-Cuellar MP, Steger J, Fuller E, Hetzner K, Slany RK · Haematologica 100:905-913 2015What this evidence cannot show
Abstract read this cycle. Murine Hoxa9-driven myeloid leukaemia. This paper does NOT measure localisation and is not cited as though it does; it establishes the other three functions, which is the premise for why a fourth would matter.
Evidence that argues against this (1)
- If the nuclear-retention function does not hold for PBX3/MEIS1, the interface still carries three functions and the target profile is unchanged - so this entry's contribution is an unmeasured possible bonus, not a load-bearing part of the interface argument. Berthelsen J et al. 1999
PBC-class nuclear retention is partner-conditional; never measured for PBX3 in any haematopoietic cell
predicts MEIS1 is what keeps PBX3 nuclear, by blocking export, as PREP1 does for PBX1
would add a fourth separable function to the MEIS1-PBX3 interface if it holds
the predicted fourth function; explicitly unmeasured for this pair