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Based on my review of the GO-CAM model gomodel:65d7e4ac00001732 "Activation of GPR75 by CCL5 in neurons (Human)" and relevant guidelines, here is my assessment:

GO-CAM Review for model:65d7e4ac00001732

Model Overview

This GO-CAM describes the activation of GPR75 (O95800) by the chemokine CCL5 (P13501) and subsequent signaling through MAP kinases in neurons. The model consists of four molecular activities linked through causal relationships.

Positive Aspects

  1. Appropriate molecular functions: The model correctly assigns molecular functions to each protein:
  2. CCL5 is annotated with chemokine activity (GO:0008009)
  3. GPR75 is annotated with G protein-coupled receptor activity (GO:0004930)

  4. MAPK1 and MAPK3 are annotated with protein serine/threonine kinase activity (GO:0004674)

  5. Correct cellular components: The cellular locations are appropriate:

  6. CCL5 in extracellular space (GO:0005615)
  7. GPR75 in plasma membrane (GO:0005886)

  8. MAPK1 and MAPK3 in cytoplasm (GO:0005737)

  9. Biological processes: The model connects activities to relevant biological processes:

  10. CCL5 to positive regulation of G protein-coupled receptor signaling (GO:0045745)
  11. GPR75 to G protein-coupled receptor signaling pathway (GO:0007186)

  12. MAPK1 and MAPK3 to ERK1 and ERK2 cascade (GO:0070371)

  13. Evidence: All claims are supported by literature evidence, primarily PMID:29772059 which specifically describes CCL5 activation of GPR75 leading to ERK1/2 activation.

Areas for Improvement

  1. Signaling pathway completeness: The model correctly shows CCL5 directly positively regulating (RO:0002629) GPR75, and GPR75 has input for (RO:0002407) both MAPK3 and MAPK1. However, the model could benefit from:
  2. Including the intermediate G protein components between GPR75 and the MAP kinases

  3. According to PMID:29772059, GPR75 activates a Gq signaling pathway which triggers PI3K and phospholipase C, ultimately leading to ERK activation

  4. Relationship between MAPK3 and MAPK1:

  5. The model shows both MAPK3 and MAPK1 as direct targets of GPR75 but doesn't capture their relationship to each other in the kinase cascade

  6. According to the cited literature, there is typically a hierarchical activation where MAPK3 (ERK1) can activate MAPK1 (ERK2)

  7. Biological context:

  8. While the model indicates "in neurons (Human)" in the title, it would be beneficial to include a cell type annotation in the model itself

  9. The publication indicates that GPR75 activation by CCL5 promotes neuronal survival through the PI3K/AKT/MAPK pathway, which could be included as a higher-level biological process

  10. Missing components:

  11. The PI3K-AKT pathway is mentioned in the literature as being activated by CCL5-GPR75 interaction but is not represented in the model
  12. Downstream effects on neuronal survival are not captured

Consistency with GO-CAM Guidelines

Based on the "Signaling receptor activity annotation guidelines," this model follows many best practices: - Correctly shows the ligand (CCL5) in extracellular space - Uses "directly positively regulates" between ligand and receptor - Places the receptor in the plasma membrane - Uses "has input for" from receptor to its effectors

However, according to the guidelines, "the input (target) of the receptor is the effector protein it regulates," and "the causal relation between the MF of the receptor and the MF of its target is 'directly positively regulates'." In this model, GPR75 uses "has input for" (RO:0002407) rather than "directly positively regulates" (RO:0002629) for its relationship with MAPK1 and MAPK3.

Conclusion and Recommendations

The model provides a sound representation of CCL5 activation of GPR75 and subsequent MAPK signaling based on strong evidence. To improve the model, I recommend:

  1. Include the G protein intermediates between GPR75 and MAPKs (particularly Gq proteins)
  2. Add the PI3K-AKT pathway mentioned in the literature
  3. Change the relationship from GPR75 to MAPKs from "has input for" to "directly positively regulates" for consistency with GO-CAM guidelines
  4. Consider adding neuronal survival as a downstream biological process
  5. Add a cell type annotation to specify neuronal context
  6. Consider showing the hierarchical relationship between MAPK3 and MAPK1

These changes would create a more complete representation of the signaling pathway while maintaining consistency with GO-CAM best practices.