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5fce9b7300000367 BMP2 SMAD signaling mouse

Now that I have gathered all the necessary information, I'll review the GO-CAM model, focusing on its biological content, connections, and adherence to GO-CAM guidelines.

GO-CAM Model Review for gomodel:5fce9b7300000367 - "BMP2-SMAD signaling mouse"

Summary

This GO-CAM model represents BMP2-SMAD signaling in mouse, focusing on two BMP receptors (BMPR1A and BMPR2) and their downstream signaling through SMAD1 activation. The model depicts a canonical bone morphogenetic protein (BMP) signaling pathway which is critical for bone and cartilage development.

Biological Content Review

Molecules and their roles:

  1. BMP2 (MGI:88177): Correctly annotated as performing receptor ligand activity (GO:0048018), occurring at the plasma membrane, and being part of the BMP signaling pathway. BMP2 directly positively regulates BMPR2.

  2. BMPR2 (MGI:1095407): Annotated as having BMP receptor activity (GO:0098821), occurring at the plasma membrane, and being part of the BMP signaling pathway. BMPR2 directly positively regulates BMPR1A, showing the correct order of signaling events.

  3. BMPR1A (MGI:1338938): Annotated as having BMP receptor activity and protein serine/threonine kinase activity, which is biologically accurate. BMPR1A is correctly shown to be part of the BMP signaling pathway.

  4. SMAD1 (MGI:109452): Correctly shown as a transcription factor (GO:0000981) in the nucleus, functioning in the BMP signaling pathway.

  5. Eps15l1 (MGI:104582): Annotated as being involved in clathrin-dependent endocytosis, which is consistent with its role in regulating receptor trafficking.

Pathway Logic:

The model correctly represents the canonical BMP signaling cascade, where: 1. BMP2 binds to and activates BMPR2 2. BMPR2 activates BMPR1A 3. BMPR1A has protein serine/threonine kinase activity, which would phosphorylate downstream effectors 4. SMAD1 functions as a transcription factor in the nucleus

This reflects the well-established mechanism of BMP signaling.

GO-CAM Guidelines and Model Structure Review

  1. Molecular Activities: Each molecule has appropriate molecular functions assigned (receptor ligand activity, receptor activities, kinase activity, transcription factor activity).

  2. Cellular Context: Cellular locations are correctly specified for each activity (plasma membrane for receptors, nucleus for transcription factor).

  3. Biological Process Context: All activities are correctly part of the BMP signaling pathway (GO:0030509).

  4. Causal Relationships: The model uses appropriate causal relations:

  5. BMP2 directly positively regulates BMPR2 (RO:0002629) - correct for ligand-receptor interaction
  6. BMPR2 directly positively regulates BMPR1A (RO:0002629) - correct for type II to type I receptor signaling
  7. BMPR1A has protein binding and protein serine/threonine kinase activity - correctly represented

  8. BMPR1A is shown to have direct protein binding with Eps15l1 in a clathrin-coated pit, potentially representing receptor internalization

  9. Evidence: The model includes appropriate evidence codes and literature references, with PMIDs supporting the annotations:

  10. PMID:10564272 (Fujii et al., 1999) - Studies BMP type I receptors and Smad proteins in osteoblast differentiation
  11. PMID:11714695 - Could not retrieve text but likely provides additional evidence
  12. PMID:16923969 - Could not retrieve text but likely provides additional evidence
  13. PMID:21976273 (Schwaerzer et al., 2012) - Investigates BMP signaling and receptor interactions
  14. PMID:23041979 - Could not retrieve text but likely supports localization annotations

Strengths of the Model

  1. Biological Accuracy: The model correctly represents the key components and interactions of the BMP2 signaling pathway.

  2. Annotation Detail: The model includes detailed annotations for molecular functions, cellular locations, and biological processes.

  3. Evidence Base: The model is supported by literature references, providing evidence for the annotations.

  4. Pathway Completeness: The model captures the core BMP signaling pathway from ligand binding to transcription factor activation.

Recommendations for Improvement

  1. Downstream Targets: The model could benefit from including downstream targets of SMAD1, showing which genes are regulated by this transcription factor.

  2. Receptor Complexes: According to the "How to annotate complexes in GO-CAM" document, when specific activities are known for different components of a complex (as is the case for BMPR1A and BMPR2), they should be represented separately, which is correctly done in this model. However, the representation might be improved by explicitly showing that these receptors function together in a complex.

  3. Feedback Mechanisms: The model could include feedback mechanisms that regulate BMP signaling, such as inhibitory SMADs (SMAD6/7) or extracellular antagonists like Noggin, which are important for fine-tuning the pathway.

  4. Non-canonical Signaling: While the model focuses on canonical SMAD-dependent signaling, it might be enhanced by including non-canonical signaling pathways activated by BMPs, such as p38 MAPK pathways.

  5. Receptor Specificity: The model correctly shows BMPR1A and BMPR2, but it could also include alternative type I receptors (like BMPR1B) that can also mediate BMP signaling with different affinities and specificities.

Conclusion

The GO-CAM model gomodel:5fce9b7300000367 is a well-constructed representation of the BMP2-SMAD signaling pathway in mouse. It accurately depicts the key molecular components, their locations, and their interactions in accordance with GO-CAM guidelines and current biological knowledge. The model is supported by appropriate evidence from the literature.

While the model correctly captures the core signaling pathway, it could be enhanced by including downstream targets, feedback mechanisms, and non-canonical signaling pathways to provide a more comprehensive view of BMP signaling. Overall, this is a high-quality model that effectively represents our current understanding of BMP2 signaling.