Post-translational modification of β-catenin by O-glycosylation regulates its nuclear localization and transcriptional activity
Bibliographic record
Abstract
4515 β-catenin is a multifunctional protein that serves a structural role at cell-cell adherens junctions and a regulatory function as a transcriptional activator mediating Wnt signal transduction. The proliferative effects of Wnt signaling are achieved by stabilization of cytosolic β-catenin, permitting accumulation of the protein and its subsequent translocation to the nucleus where it forms complexes with members of the TCF/LEF family of transcription factors to activate gene transcription. Cytosolic levels of β-catenin are tightly regulated by phosporylation; however, the mechanism(s) responsible for β-catenin nuclear entry is not well understood. Recently, β-catenin was reported to be modified post-translationally by O-glycosylation in breast cancer cells exposed to the intracellular calcium pump inhibitor, thapsigargin (TG). This type of modification involves attachment of β-N-acetylglucosamine (GlcNAc) to serine/threonine residues via an O-glycosidic linkage. In the present study, we demonstrate that β-catenin is modified by at least two distinct patterns of O-glycosylation: one that is recognized by the lectin, wheat germ agglutinin (WGA; w-O-GlcNAc), and another that is detected by a monoclonal antibody specific for O-GlcNAc modification (α-RL-2; r-O-GlcNAc). To evaluate whether O-glycosylation of β-catenin influences its signaling properties, we investigated β-catenin O-GlcNAc status in several cell lines, including the normal breast cell line, MCF-10A, and the breast tumor lines, MCF-7 and MDA-MB-231. These studies revealed that a significant amount of β-catenin in MCF-10A cells is glycosylated in a w-O-GlcNAc manner, while the cancer cells possessed negligible quantities of the w-O-GlcNAc-modified protein. In contrast, r-O-GlcNAc-modified β-catenin was detected at comparable levels in the three cell lines examined. Assessment of β-catenin status in nuclear extracts revealed the protein to be more abundant in the nucleus of the MCF-7 and MDA-MB-231 tumor cells than in normal MCF-10A cells, while w-O-GlcNAc-modified β-catenin was not observed in nuclear fractions prepared from any of the tested cell lines. Treatment of MCF-7 cells with TG induced a time-dependent increase in the abundance of w-O-GlcNAc-modified β-catenin. This increase in the w-O-GlcNAc-modified form of the protein was accompanied by a progressive decrease in its nuclear localization. TG treatment also resulted in an apparent suppression of β-catenin transcriptional activity, as evidenced by the dramatic reduction in the expression of cyclin D1, a major target of β-catenin transcriptional regulation. Collectively, our results suggest that w-O-glycosylation of β-catenin may represent a novel mechanism important in regulation of β-catenin nuclear localization and transcriptional activity.
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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 | 0.000 |
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 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".