Noncanonical WNT‐5A signaling regulates TGF‐β‐induced extracellular matrix production by airway smooth muscle cells
Bibliographic record
Abstract
Transforming growth factor β (TGF‐β), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF‐β‐induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF‐β and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT‐5A being the most profoundly expressed. Interestingly, WNT‐5A shows ~2‐fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT‐5A is markedly induced in response to TGF‐β (4–16‐fold; EC 50 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT‐5A engages noncanonical WNT signaling pathways, as inhibition of Ca 2+ and c‐Jun N‐terminal kinase (JNK) signaling attenuated this TGF‐β response, whereas the canonical WNT antagonist Dickkopf 1 (DKK‐1) did not. Accordingly, WNT‐5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT‐5A receptors Frizzled 8 (FZD 8 ) and RYK attenuated TGF‐β‐induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT‐5A signaling is activated by and necessary for TGF‐β‐induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.—Kumawat, K., Menzen, M. H., Bos, I. S. T., Baarsma, H. A., Borger, P., Roth, M., Tamm, M., Halayko, A. J., Simoons, M., Prins, A., Postma, D. S., Schmidt, M., and Gosens, R. Noncanonical WNT‐5A signaling regulates TGF‐β‐induced extracellular matrix production by airway smooth muscle cells. FASEB J. 27, 1631–1643 (2013). www.fasebj.org
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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".