Binding of Hypoxia-Induced Mitogenic Factor/RELM-β to Bone Morphogenetic Protein Receptor 2 Complex Promotes Pulmonary Hypertension
Bibliographic record
Abstract
BACKGROUND: HIMF (hypoxia-induced mitogenic factor) induces pulmonary hypertension; however, the molecular nature of its extracellular membrane receptor(s) remains unknown. METHODS: A combination of cross-immunoprecipitation and immunoblotting, yeast 2-hybrid assays, and proteomics analysis was performed to screen and identify the candidate receptors. The interaction of HIMF with these candidate(s) was further evaluated using overexpression, silencing, point mutation, and blocking peptide strategies in chronic hypoxia and sugen/hypoxia pulmonary hypertension rat models to decipher the underlying pathophysiologic mechanisms. RESULTS: Cross-immunoprecipitation and immunoblotting identified HIMF interaction with the BMPR2 (bone morphogenetic protein receptor 2) complex. Yeast 2-hybrid revealed HIMF binding to the DTLPF motif (Asp-Thr-leucine-Pro-Phe [aspartic acid-threonine-leucine-proline-phenylalanine]) at the 54 to 58 amino acids (aa) in the extracellular domain of the BMPR1A (bone morphogenetic protein receptor 1A), one partner of the BMPR2 heterodimeric complex, but not BMPR2 itself. HIMF and human counterpart RELM (resistin-like molecule)-β binding to BMPR1A disrupted the BMPR1A/BMPR2 complex and decreased BMPR2 activity as revealed by reduced downstream events including ≈43% to 56% decline in Smad1/5/9 (Sma- and Mad-related protein 1/5/9) phosphorylation and ≈41% to 60% decrease in Id-1 (inhibitor of DNA binding 1) expression. This dynamic induced pulmonary artery smooth muscle cell proliferation and pulmonary vascular remodeling leading to pulmonary hypertension. A mutated motif in rats or a blocking peptide targeting this motif restrained HIMF binding with BMPR1A, rescued BMPR2 activity by ≈25% increase in Smad/1/5/9 phosphorylation and ≈39% elevation in Id-1 expression, and attenuated chronic hypoxia or sugen/hypoxia-induced pulmonary hypertension. CONCLUSIONS: HIMF induced pulmonary hypertension by direct binding to BMPR1A ectodomain, subsequently disrupting its binding to BMPR2 and BMPR2 activity. This HIMF signaling pathway represents a potential therapeutic target by selectively interfering with BMPR1A binding.
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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) | 0.002 | 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".