Skip to content

Now let me review the GO-CAM model gomodel:6606056e00001507 based on the information I've gathered.

Review of GO-CAM Model: gomodel:6606056e00001507

Overview of the Model

This model is titled "TREM2 activated by APOA2. (Human)" and describes an important signaling pathway in human microglia that is relevant to Alzheimer's disease pathogenesis. It represents how Apolipoprotein A-II (APOA2) activates the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which leads to downstream signaling through the TYROBP/DAP12 adaptor protein and SYK kinase activity.

Model Components

The model contains four key activities:

  1. APOA2 (P02652) - Receptor ligand activity (GO:0048018) occurring in extracellular space
  2. TREM2 (Q9NZC2) - Transmembrane signaling receptor activity (GO:0004888) occurring in plasma membrane
  3. TYROBP/DAP12 (O43914) - Protein-macromolecule adaptor activity (GO:0030674) occurring in plasma membrane
  4. SYK (P43405) - Protein tyrosine kinase activity (GO:0004713) occurring in cytoplasm

Causal Relationships

The model includes causal relationships that describe the following pathway: - APOA2 ligand (GO:0048018) → directly positively regulates (RO:0002629) → TREM2 receptor (GO:0004888) - TREM2 receptor (GO:0004888) → directly positively regulates (RO:0002629) → TYROBP adaptor (GO:0030674) - TYROBP adaptor (GO:0030674) → directly positively regulates (RO:0002629) → SYK kinase (GO:0004713)

Biological Context

The activities are placed in the context of two biological processes: - Cellular response to lipoprotein particle stimulus (GO:0071402) - Cellular response to amyloid-beta (GO:1904646)

Evidence and Provenance

The model uses high-quality evidence from experimental studies: - Direct assay evidence (ECO:0000314) from published literature (PMID:27477018, PMID:23459077, PMID:29518356) - Sequence similarity evidence (ECO:0000250) for some aspects (particularly SYK activity) - Annotations are from the contributor with ORCID 0000-0001-8769-177X, dated April 4, 2024

Assessment

Accuracy and Biological Content

The model accurately represents a signaling pathway that has been well-documented in the literature. Based on the PMID:29518356 ("TREM2 is a receptor for beta-amyloid which mediates microglial function"), TREM2 has been shown to bind to APOA2 and other apolipoproteins to facilitate uptake of amyloid-beta by microglia. This paper specifically demonstrates:

  1. TREM2 binds to apolipoproteins including APOA2
  2. This binding enhances TREM2 interaction with DAP12 (TYROBP)
  3. This leads to downstream phosphorylation of SYK

The model correctly represents these relationships with appropriate GO terms and causal relationships.

Adherence to GO-CAM Best Practices

The model follows GO-CAM best practices for representing complexes and signaling pathways:

  1. Representation of activities: Each protein is appropriately annotated with a specific molecular function that it performs.

  2. Causal relationships: The model uses correct causal relationship predicates (RO:0002629 "directly positively regulates") to connect the activities in a directional manner.

  3. Cellular contexts: Each activity is appropriately annotated with a cellular component to indicate where it occurs.

  4. Biological processes: The activities are connected to relevant biological processes.

  5. Evidence: Each assertion is supported by appropriate evidence codes and references.

  6. Complex representation: The model correctly follows the recommendations for annotating activities in the context of complexes. Since the specific molecular functions carried out by each component (TREM2, TYROBP, SYK) are known, they are individually represented rather than using a complex GO term, which aligns with guideline #1 from the "How to annotate complexes in GO-CAM" document.

Areas for Improvement

While the model is generally well-constructed, I would suggest a few potential enhancements:

  1. Additional molecular context: The model could potentially be expanded to include the known binding of amyloid-beta to TREM2, which is a key aspect described in PMID:29518356. This would provide more complete molecular context for the pathway.

  2. Downstream effects: The model could be extended to include downstream effects of SYK activation, such as phosphorylation of specific targets or activation of specific pathways that lead to microglial activation, which are mentioned in the literature.

  3. Additional processes: The model could be connected to additional relevant biological processes such as phagocytosis or inflammatory response, which are known outcomes of this signaling pathway.

Conclusion

The GO-CAM model gomodel:6606056e00001507 accurately represents the signaling pathway where APOA2 activates TREM2, leading to signaling through TYROBP and SYK in human cells. It adheres to GO-CAM best practices and is supported by high-quality experimental evidence. This pathway is of significant biomedical relevance as it plays a role in microglial responses to amyloid-beta in Alzheimer's disease. The model could be further enhanced by including additional molecular context and downstream effects as described in the literature.