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Now I'll review the GO-CAM model with ID gomodel:5fce9b7300002436.

Review of GO-CAM Model (gomodel:5fce9b7300002436)

Model Overview

This model titled "TREM2 activated by APP" describes a signaling pathway involving TREM2 (Triggering Receptor Expressed on Myeloid cells 2), its adaptor protein DAP12 (TYROBP), and downstream tyrosine kinase SYK in human cells (NCBITaxon:9606).

Components and Structure

The model contains four main molecular activities:

  1. APP (UniProtKB:P05067) with receptor ligand activity (GO:0048018) occurring in extracellular space (GO:0005615), part of cellular response to amyloid-beta (GO:1904646)
  2. TREM2 (UniProtKB:Q9NZC2) with transmembrane signaling receptor activity (GO:0004888) occurring in plasma membrane (GO:0005886), part of cellular response to amyloid-beta (GO:1904646)
  3. TYROBP/DAP12 (UniProtKB:O43914) with protein-macromolecule adaptor activity (GO:0030674) occurring in plasma membrane (GO:0005886), part of cellular response to amyloid-beta (GO:1904646)
  4. SYK (UniProtKB:P43405) with protein tyrosine kinase activity (GO:0004713) occurring in cytoplasm (GO:0005737), part of cellular response to amyloid-beta (GO:1904646)

Causal Relationships

The model represents the following causal flow: - APP directly positively regulates (RO:0002629) TREM2 - TREM2 directly positively regulates (RO:0002629) TYROBP/DAP12 - TYROBP/DAP12 directly positively regulates (RO:0002629) SYK

Evidence

Each activity and causal relationship is supported by experimental evidence from peer-reviewed literature (ECO:0000314 - direct assay evidence used in manual assertion), primarily from PMID:29518356 for most connections and additional PMID:24078628 for TREM2 localization and PMID:23459077 for TYROBP/DAP12 activity and localization.

Assessment and Recommendations

Strengths of the model:

  • The model accurately captures the molecular function of each protein
  • The causal relationships are appropriately represented with the correct relationship types
  • All activities are properly classified as part of the same biological process
  • Evidence is well-documented for each assertion
  • The model aligns with current literature showing TREM2 as a receptor for amyloid-beta (supported by PMID:29518356)

Areas for improvement:

  1. Complex representation:

  2. The model currently doesn't indicate that TREM2 and DAP12/TYROBP form a complex, which is critical for signaling. According to GO-CAM complex guidelines, this should be represented since they function together to transmit the signal to SYK.

  3. Physical interactions:

  4. The direct physical interaction between TREM2 and its adaptor DAP12/TYROBP should be more explicitly represented, as this binding is crucial for signal transduction.

  5. Additional downstream effects:

  6. The model could be extended to include downstream effects after SYK activation, such as phosphorylation of specific targets and activation of inflammatory responses.

  7. Specificity of cellular context:

  8. While the model indicates that TREM2 is in the plasma membrane, it would be useful to specify that this is occurring specifically in microglial cells (or other myeloid cells), which is the primary cell type expressing TREM2 in the brain.

  9. Additional evidence:

  10. The model could benefit from including more recent publications that further support the interactions between Aβ, TREM2, and downstream signaling.

Suggested Updates

  1. Add a relationship indicating that TREM2 and DAP12/TYROBP form a functional complex through their physical association.

  2. Consider adding details about the specific molecular mechanisms of activation, such as:

  3. Phosphorylation of ITAM domains in DAP12/TYROBP following ligand binding to TREM2

  4. Recruitment of SYK to phosphorylated ITAM domains

  5. Include more specific cellular context information about the pathway occurring in microglia.

  6. Extend the model to capture downstream effects of SYK activation in the context of amyloid-beta response.

Conclusion

Overall, the model gomodel:5fce9b7300002436 provides a solid representation of the TREM2 signaling pathway activated by APP/amyloid-beta, which is consistent with current literature. The model accurately captures the main molecular players in the pathway and their causal relationships. The suggested improvements would enhance the model's completeness and provide a more comprehensive view of the biological mechanisms involved in TREM2-mediated responses to amyloid-beta, which is relevant for understanding microglial function in Alzheimer's disease.

The model correctly follows GO-CAM best practices in terms of evidence documentation and causal relationship representation. The suggested addition of complex information would further align the model with GO-CAM guidelines for representing protein complexes in signaling pathways.