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After researching the GO-CAM model and relevant documentation, I'm now ready to provide a comprehensive review of the GO-CAM model with ID "600ced8500002343" titled "BMP9 signaling pathway (Human)".

Review of GO-CAM Model: BMP9 signaling pathway (Human)

Model ID: gomodel:600ced8500002343

Summary of the Model

This model represents the BMP9 signaling pathway in humans, showing how BMP9 (GDF2) activates its receptors and triggers downstream signaling. The pathway includes:

  1. BMP9/GDF2 (UniProtKB:Q9UK05) acting as a growth factor
  2. Type II receptors: ACVR2B (UniProtKB:Q13705) and BMPR2 (UniProtKB:Q13873)
  3. Type I receptor: ACVRL1/ALK1 (UniProtKB:P37023)
  4. Downstream effector: SMAD1 (UniProtKB:Q15797)

Strengths of the Model

  1. Accurate representation of pathway components: The model correctly includes the main components of the BMP9 signaling pathway.
  2. Proper cellular localization: The model appropriately places components in their correct cellular locations (BMP9 in extracellular space, receptors in plasma membrane).
  3. Correct pathway association: All activities are properly associated with the BMP signaling pathway (GO:0030509).
  4. Evidence support: Each activity and relationship is supported by evidence from peer-reviewed literature.
  5. Directionality of signaling: The model correctly shows the flow of information from ligand to downstream effector.

Issues and Suggestions for Improvement

1. Relationship between GDF2 and its receptors

The model shows GDF2 directly positively regulating both ACVR2B and BMPR2. According to the "Signaling receptor activity annotation guidelines", the relationship between a ligand and its receptors should be represented using the predicate "directly positively regulates". This is correctly implemented in the model.

2. Relationship between type II and type I receptors

The model shows both type II receptors (ACVR2B and BMPR2) directly positively regulating the type I receptor ACVRL1, which is consistent with the known mechanism where type II receptors phosphorylate and activate type I receptors in the BMP signaling pathway.

3. Missing parts of the signaling pathway

While the model captures the main components, I recommend adding:

  • The formation of the receptor complex between type I and type II receptors upon BMP9 binding
  • The SMAD1 transcription factor activity leads to transcriptional regulation of target genes
  • The model could benefit from depicting additional SMAD proteins (SMAD4, SMAD5) that form complexes with SMAD1

4. Missing input relationships

According to the guidelines, receptors should have their downstream targets identified via "has input" relationships. While the causal associations are correct, the explicit input relationships could be made clearer.

5. Other BMPs and their signaling

The model focuses exclusively on BMP9/GDF2, but other BMPs (like BMP10) can also signal through these receptors. Consider mentioning this in a note or expanding the model to include alternative ligands.

Verification with Literature

The model is well-supported by literature evidence. I've verified key aspects:

  1. PMID:7664647 and PMID:19366699 support GDF2/BMP9 as activating BMPR2 and ACVR2B receptors
  2. PMID:8622651 and PMID:8395525 support ACVR2B function in this pathway
  3. PMID:22718755 confirms ACVRL1/ALK1 as the type I receptor in this cascade
  4. PMID:8653785 supports SMAD1's role as a downstream effector

This is consistent with current understanding of the BMP9 signaling pathway, where BMP9 binds to type II receptors (ACVR2B or BMPR2), which then phosphorylate and activate the type I receptor ACVRL1/ALK1, which in turn phosphorylates and activates SMAD1 to regulate gene expression.

Conclusion

The GO-CAM model "600ced8500002343" accurately represents the core BMP9 signaling pathway in humans, with proper molecular functions, cellular locations, and causal relationships. The model follows GO-CAM best practices for representing signaling pathways.

Recommendations for improvement: 1. Consider adding additional downstream components (e.g., SMAD4 complex formation) 2. Clarify the input relationships for the receptors 3. Add more detail about the transcriptional targets regulated by SMAD1 4. Consider including notes about alternative ligands (like BMP10) that can act through the same pathway

Overall, this is a well-constructed model that provides a clear representation of the BMP9 signaling pathway.