Fibulin‐4 and latent‐transforming growth factor beta‐binding protein‐4 interactions with syndecan‐2 and syndecan‐3 are required for elastogenesis
Bibliographic record
Abstract
Elastogenesis is a cell surface-located hierarchical process that requires the core components tropoelastin and fibrillins and several accessory proteins, including fibulin-4 (FBLN4) and latent TGF-β binding protein-4 (LTBP4). FBLN4 and LTBP4 interact with cells, but their cell receptors and associated molecular elastogenic mechanisms remain unknown. Primary skin fibroblasts and several vascular smooth muscle cells bound strongly to FBLN4 multimers and LTBP4 monomers. We identified two cell interaction epitopes on FBLN4 located in cbEGF2-3 and the C-terminal domain, whereas FBLN4 multimerization sites were mapped to cbEGF4-5 and the C-terminal domain. We also determined a novel cell interaction site in the N-terminal half of LTBP4. Cell binding to FBLN4 and LTBP4 was strongly inhibited in the presence of heparin, heparan sulfate, or after enzymatic removal of heparan sulfate, suggesting heparan sulfate proteoglycans as relevant cell surface receptors. siRNA knockdown experiments identified syndecan (SDC)2 and SDC3 as cell receptors for FBNL4 and SDC3 for LTBP4. Direct protein interactions between FBLN4 and the recombinant ectodomains of SDC2 and SDC3, and between LTBP4 and SDC3 validated these results. Interaction of the elastogenic cells with FBLN4 and LTBP4 enhanced elastogenesis, whereas SDC2 and/or SDC3 knockdowns led to reduced elastic fiber formation. The cell interactions with FBLN4 and LTBP4 significantly enhanced focal adhesion formation, induced cell contraction, and led to activation of focal adhesion kinase (FAK), Erk1/2, and RhoA. Pharmacological inhibition of these effectors markedly attenuated elastic fiber formation, and siRNA knockdown of SDC2 and SDC3 led to reduced levels of pFAK, pERK, and active RhoA. Together, these data demonstrate that FBLN4 and LTBP4 cell interactions through SDC2 and SDC3 promote elastogenesis by enhancing focal adhesion formation, leading to cell contractility through FAK, Erk1/2, and RhoA activation, underscoring the significance of these pathways in elastogenesis.
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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 | 0.000 | 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 | 0.001 | 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".