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GO-CAM Model Review: gomodel:5fce9b7300000434 (BMP2-MAPK signaling mouse)

Summary

The model gomodel:5fce9b7300000434 represents BMP2-MAPK signaling in mouse. It illustrates the signaling pathway from BMP2 (as a ligand) through BMP receptors, leading to MAPK cascade activation and subsequently affecting transcription factors and other proteins involved in osteoblast differentiation and bone development.

Strengths of the Model

1. Appropriate pathway representation: The model correctly depicts the BMP signaling pathway starting with BMP2 (MGI:MGI:88177) as a receptor ligand, properly activating BMP receptors (BMPR1A, BMPR1B, BMPR2), and leading to downstream activation of MAPK components.

2. Evidence-based annotations: Most causal relationships are supported by experimental evidence (primarily ECO:0000314 - direct assay evidence) and have appropriate literature references.

3. Proper cellular localization: The model includes appropriate cellular compartments (extracellular region for BMP2, cytosol for MAPK components).

4. Biological process associations: Activities are correctly placed within relevant biological processes (BMP signaling pathway, MAPK cascade, osteoblast differentiation).

Issues and Recommendations for Improvement

1. Missing BMP Receptor Complex Formation and Structure

According to the "How to annotate complexes in GO-CAM" document, when modeling receptor complexes where different subunits have different activities, each component should be represented with its specific activity. The current model represents BMPR1A (MGI:MGI:1338938), BMPR1B (MGI:MGI:107191), and BMPR2 (MGI:MGI:1095407) correctly with their respective activities, but does not clearly represent their functioning as a complex.

Recommendation: Consider using BFO:0000051 (has_part) relations between receptor components to better represent the BMP receptor complex formation.

2. Conformance with Signaling Receptor Annotation Guidelines

Based on the "Signaling receptor activity annotation guidelines," the model correctly shows: - BMP2 enabling receptor ligand activity (GO:0048018) - BMP receptors (BMPR1A/B) with "BMP receptor activity" (GO:0098821) - Appropriate causal relations with RO:0002629 (directly positively regulates)

However, there are some deviations:

a. Receptor inputs: According to the guidelines, "The input (target) of the receptor is the effector protein it regulates... Note that the input (target) of the receptor is NOT its ligand." The current model doesn't explicitly capture this using input relations.

Recommendation: Add has_input relations from the BMP receptors to their downstream effectors (Map3k7).

b. BMP binding activities: Both BMPR1A and BMPR1B are shown with "BMP binding" (GO:0036122) activity, but these should be considered as part of their receptor function rather than separate activities.

Recommendation: Consider removing the separate BMP binding activities or clarify their role in the signaling process.

3. Missing Evidence for Some Annotations

Several activities and causal associations lack evidence codes: - Activity gomodel:5fce9b7300000434/5fce9b7300000840 (Bglap with structural constituent of bone activity) - Activity gomodel:5fce9b7300000434/5fce9b7300000795 (BMPR1A with protein serine/threonine kinase activity) - Several causal associations (e.g., between gomodel:5fce9b7300000434/5fce9b7300000830 and gomodel:5fce9b7300000434/5fce9b7300000840)

Recommendation: Add appropriate evidence codes and references for these annotations.

4. Pathway Flow Consistency

The model depicts the BMP signaling pathway leading to activation of transcription factors (Runx2, Sp7) and ultimately to bone-related proteins (Ibsp, Bglap). However, some of the causal relationships could be clarified:

a. Jumping connections: The causal relationship from Runx2 (GO:0003700) directly to structural constituent of bone activity (GO:0008147) skips intermediate steps.

Recommendation: Consider adding intermediate steps that explain how Runx2 regulates Bglap expression.

b. Redundant connections: BMPR1A and BMPR1B both activate Map3k7, but the pathways could be more clearly delineated.

Recommendation: Consider revising the connections to better represent the specificity of signaling pathways.

5. Feedback Mechanisms

Based on the literature reviewed (particularly PMID:21976273), BMP signaling includes feedback mechanisms involving noggin, which is not represented in the model.

Recommendation: Consider adding relevant feedback mechanisms to provide a more complete representation of the pathway regulation.

Scientific Content Verification

The scientific content aligns well with current knowledge of BMP-MAPK signaling:

1. The paper by Schwaerzer et al. (PMID:21976273) confirms the role of BMP2 in activating Smad and non-Smad (p38 MAPK) signaling pathways, which is correctly represented in the model.

2. The involvement of MAPK components (Map3k7, Map2k6, Mapk11, Mapk14) in mediating BMP signaling to transcription factors is supported by the literature.

3. The downstream effects on osteoblast differentiation and bone development proteins (Alpl, Sp7, Ibsp, Bglap) are consistent with the known roles of BMP signaling in bone development.

Conclusion

Overall, gomodel:5fce9b7300000434 provides a good representation of BMP2-MAPK signaling in mouse, capturing key molecular functions, cellular components, and biological processes. The model is well-supported by experimental evidence and literature references.

The main recommendations for improvement include: 1. Better representation of receptor complex formation 2. More consistent application of signaling receptor annotation guidelines 3. Adding missing evidence codes 4. Clarifying some causal relationships 5. Including feedback mechanisms

With these improvements, the model would provide an even more comprehensive and accurate representation of BMP2-MAPK signaling.