Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A
Bibliographic record
Abstract
Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear levels of proteins that drive cancer progression and therapeutic resistance such as JUN, YAP, MYC, androgen receptor, hnRNPA1, and NF-κB under conditions where compounds that target PP2A or KPNB1 individually are inactive. These findings provide new insights into sphingolipid biology and highlight a possible path toward cancer therapeutics that could overcome drug resistance.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".