K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Full frame distilled prediction
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.
- Candidate categories
- none
- Consensus categories
- none
- Domain
- Candidate signal: noneConsensus signal: none
- Study design
- Candidate signal: Bench or experimentalConsensus signal: Bench or experimental
- Genre
- Candidate signal: EmpiricalConsensus signal: Empirical
- Teacher disagreement score
- 0.013
- Threshold uncertainty score
- 0.414
- Validation status
machine_predicted_unvalidated·codex-gemma-dda1882f352a
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)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
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.
- Teacher spread
- 0.187 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
K252a is best known as a Trk inhibitor, but is also a neuroprotective compound. CEP1347, a K252a derivative, retains neuroprotective properties, but does not inhibit TrkA. CEP1347 has recently been shown to directly inhibit MAPKKKs, including MLK3, but the effect of K252a on MAPKKKs remains unknown. K252a and CEP1347 not only prevent death, but also facilitate neurite outgrowth and maintenance, somal hypertrophy, and neurotransmitter synthesis. The biochemical basis for these trophic effects remains unknown. We have compared the effects of CEP1347 and K252a on MLK and JNK signaling and on neurotrophic pathways that support survival and growth. Our data show that K252a is a potent inhibitor of MLK3 activity in vivo and in vitro (IC(50) approximately 5 nm). However, we also found that K252a and CEP1347 activate Akt and ERK and show that blockade of phosphatidylinositol 3-kinase or MEK activity ablates the effect of K252a and CEP1347 on cell survival. Activation of Akt and ERK occurs through an MLK-independent pathway that may involve c-Src. Together, these data show that the neuroprotective and neurotrophic effects of K252a and CEP1347 involve activation of several neurotrophic signaling pathways.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- Journal of Biological Chemistry
- Topic
- Melanoma and MAPK Pathways
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- Aegera Therapeutics (Canada)McGill UniversityMontreal Neurological Institute and Hospital
- Funders
- not available
- Keywords
- Trk receptorProtein kinase BNeuroprotectionMAPK/ERK pathwayTropomyosin receptor kinase ANeurotrophinKinaseNeurotrophic factorsPI3K/AKT/mTOR pathwayNeuriteCell biologySignal transductionBiologyPharmacologyChemistryBiochemistryReceptorIn vitro
- Has abstract in OpenAlex
- yes