Intramembrane proteolysis of the p75 neurotrophin receptor is required for glioma invasion.
Bibliographic record
Abstract
B209 The p75 neurotrophin receptor is a multifunctional signaling protein that interacts with numerous ligands and coreceptors to regulate cellular survival, neurite outgrowth, myelin formation and apoptosis in others. It has recently been shown that p75NTR is a central regulator of glioma invasion which provide a very important evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas. The mechanism by which the receptor elicits the invasive effect is poorly understood. It has been shown that the full length p75NTR protein undergoes ectodomain shedding followed by regulated intramembrane proteolysis (RIP). An α-secretase-like activity cleaves p75NTR in the juxtamembrane stalk region to generate a membrane bound 24 kDa C-terminal fragment (CTF). The CTF is then processed by a presenilin-dependent γ-secretase activity to give rise to a soluble 19 kDa product (ICD). The ICD is then targeted for degradation by the proteasome. We assessed if proteolytic processing of p75 is required for glioma invasion. We found that in glioma cells, p75NTR is cleaved to generate both the 24 kDa fragment CTF and a 19 kDa ICD. Treatment of U87p75 cells with compound X, a specific inhibitor of γ-secretase, resulted in the accumulation of the 24 kDa CTF fragment without subsequent cleavage to ICD and inhibition of migration and invasion in vitro. To directly test the role of p75NTR processing in glioma invasion, we constructed chimeric proteins by replacing either the transmembrane or the extracellular stalk domain of p75NTR with equivalent domains from the Fas receptor. Both p75NTR and Fas are members of the TNF receptor superfamily, and although they each contain similar domains, unlike p75NTR, Fas does not undergo RIP. We found that expression of cleavage resistant forms of p75NTR which prevent receptor proteolysis, blocked glioma invasion in vitro and in vivo. These results indicate the p75NTR-mediated glioma invasion requires γ-secretase dependent release of its ICD. The exact mechanism by which the ICD exerts its role is still to be determined. This work highlights the possibility that[[Unsupported Character - ]] γ-secretase inhibitors may have clinical application in glioma treatment.
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.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".