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Based on my review of the model and the supporting literature, I'll now provide a comprehensive review of GO-CAM model 66e382fb00002105.

Review of GO-CAM Model: 66e382fb00002105

Model Overview

Title: BMP8A role in spermatogenesis via SMAD1, SMAD5 and SMAD9 (Human)

Taxon: Human (NCBITaxon:9606)

Status: Production

Model Architecture Summary

This GO-CAM model represents the BMP signaling pathway focusing on BMP8A's role in spermatogenesis, specifically how BMP8A activates its receptors and downstream SMAD signaling. The model includes:

  1. BMP8A (UniProtKB:Q7Z5Y6) with cytokine activity
  2. BMP receptors (BMPR2 and BMPR1A)
  3. Downstream SMAD transcription factors (SMAD1, SMAD5, SMAD9)
  4. Appropriate causal connections between these components
  5. Cellular locations for each activity

Strong Points

  1. Accurate biological pathway representation: The model correctly depicts the canonical BMP signaling pathway where:
  2. BMP8A has cytokine activity in the extracellular space
  3. BMPR2 acts as the type II receptor
  4. BMPR1A functions as the type I receptor

  5. SMAD1/5/9 are activated by BMPR1A phosphorylation and translocate to the nucleus

  6. Well-supported evidence: The model uses appropriate evidence codes and citations, including:

  7. Direct assay evidence (ECO:0000314) from primary literature sources
  8. Mutant phenotype evidence (ECO:0000315)

  9. Appropriate localization of activities in relevant cellular compartments

  10. Causal relationships: The model properly represents the causal cascade using the recommended relationships:

  11. BMP8A directly positively regulates (RO:0002629) BMPR2
  12. BMPR2 directly positively regulates (RO:0002629) BMPR1A

  13. BMPR1A directly positively regulates (RO:0002629) SMAD1/5/9

  14. Molecular Function Details: The model appropriately assigns molecular functions to each protein:

  15. BMP8A: cytokine activity (GO:0005125)
  16. BMPR2: activin receptor activity, type II (GO:0016362)
  17. BMPR1A: transforming growth factor beta receptor activity, type I (GO:0005025)

  18. SMAD1/5/9: DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981)

  19. Cellular Compartmentalization: Each protein activity is correctly placed in its cellular compartment:

  20. BMP8A in extracellular space (GO:0005615)
  21. Receptors at plasma membrane (GO:0005886)
  22. SMAD proteins in nucleus (GO:0005634)

Areas for Improvement

  1. Receptor Complex Representation:

  2. The model separately represents BMPR1A and BMPR2, which is technically correct, but it might be worth considering representing the active receptor complex in line with how BMP receptors function. According to the complexes guidance document, since the individual subunits have known activities, the current approach is acceptable.

  3. SMAD Nuclear Translocation:

  4. While the model places SMAD1/5/9 activities in the nucleus, it could more explicitly represent how phosphorylation by BMPR1A leads to their nuclear translocation.

  5. SMAD Oligomerization:

  6. The model doesn't capture the formation of SMAD complexes (with SMAD4/co-SMAD), which is an important step in the canonical BMP signaling pathway. Based on the literature (Kretzschmar et al., 1997), SMAD phosphorylation by the type I receptor leads to association with SMAD4/DPC4 and nuclear accumulation.

  7. Downstream Targets:

  8. The model focuses on the core signaling pathway but doesn't include the downstream targets of SMAD transcriptional activity relevant to spermatogenesis.

  9. Biological Process Context:

  10. While the model's title mentions spermatogenesis, there could be more specific annotation to relate the activities to specific processes in spermatogenesis.

Scientific Validity

The model is scientifically valid and well-supported by the literature. The BMP8A signaling through BMPR2/BMPR1A to activate SMAD1/5/9 is consistent with what is known about BMP signaling pathways. Based on the UniProt entry for BMP8A (Q7Z5Y6), it plays a role in spermatogenesis and initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2. The primary literature evidence (PMID:9136927) clearly supports the phosphorylation of SMAD1 by BMP type I receptors and the resulting nuclear translocation and transcriptional activity.

Recommendations

  1. Consider adding SMAD4: The model could be enhanced by including SMAD4/DPC4, which forms complexes with phosphorylated SMAD1/5/9 as demonstrated in the Kretzschmar paper.

  2. Include specific spermatogenesis-related processes: Add specific biological processes related to spermatogenesis that are regulated by this pathway.

  3. Add Id1/Id2 target genes: The PMID:15657086 and PMID:17992660 papers discuss downstream targets of BMP signaling such as Id1 and Id2, which could be added to make the model more comprehensive.

  4. Consider adding negative regulators: The pathway is also regulated by negative regulators like Smurf1 and noggin, which could be included to provide a more complete picture of BMP signaling regulation.

Conclusion

This GO-CAM model effectively represents the core BMP8A signaling pathway through its receptors to SMAD transcription factors. It follows GO-CAM best practices regarding the representation of activities, causal relationships, and cellular locations. The model is well-supported by literature evidence and provides a solid representation of this important developmental signaling pathway. With the suggested enhancements, it could provide an even more comprehensive view of BMP8A's role in spermatogenesis.