Multiple post-translational modifications regulate E-cadherin transport during apoptosis
Bibliographic record
Abstract
E-cadherin is synthesized as a precursor and then undergoes cleavage by proprotein convertases. This processing is essential for E-cadherin maturation and cell adhesion. Loss of cell adhesion causes detachment-induced apoptosis, which is called anoikis. Anoikis can be inhibited despite loss of cell-matrix interactions by preserving E-cadherin-mediated cell-cell adhesion. Conversely, acute loss of E-cadherin sensitizes cells to apoptosis by unknown post-translational mechanisms. After treatment of breast cancer cells with drugs, we found that two independent modifications of E-cadherin inhibit its cell surface transport. First, O-linked β-N-acetylglucosamine (O-GlcNAc) modification of the cytoplasmic domain retains E-cadherin in the endoplasmic reticulum. Second, incomplete processing by proprotein convertases arrests E-cadherin transport late in the secretory pathway. We demonstrated these E-cadherin modifications (detected by specific lectins and antibodies) do not affect binding to α-catenin, β-catenin or γ-catenin. However, binding of E-cadherin to Type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), a protein required for recruitment of E-cadherin to adhesion sites, was blocked by O-GlcNAc glycosylation (O-GlcNAcylation). Consequently, E-cadherin trafficking to the plasma membrane was inhibited. However, deletion mutants that cannot be O-GlcNAcylated continued to bind PIPKIγ, trafficked to the cell surface and delayed apoptosis, confirming the biological significance of the modifications and PIPKIγ binding. Thus, O-GlyNAcylation of E-cadherin accelerates apoptosis. Furthermore, cell-stress-induced inactivation of proprotein convertases, inhibited E-cadherin maturation, further exacerbating apoptosis. The modifications of E-cadherin by O-GlcNAcylation and lack of pro-region processing represent novel mechanisms for rapid regulation of cell surface transport of E-cadherin in response to intoxication.
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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 | 0.001 | 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".