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Based on my review of the GO-CAM model "Signaling by Secretin/SCT mediated by SCTR receptor (Human)" and related documents, I'll provide a comprehensive QC review.

GO-CAM Review: Signaling by Secretin/SCT mediated by SCTR receptor (Human) gomodel:66e382fb00002293

Overview

This GO-CAM model represents the signaling pathway initiated by the binding of secretin (SCT) to its receptor (SCTR), leading to G protein activation, adenylyl cyclase stimulation, and cAMP production in human cells. The model captures a canonical G protein-coupled receptor (GPCR) signaling pathway with appropriate molecular activities, cellular locations, and causal relationships.

Strengths

  1. Adherence to GO-CAM Structure: The model appropriately represents a complete signaling pathway from ligand binding through second messenger production.

  2. Appropriate Molecular Functions:

  3. SCT has hormone activity (GO:0005179)
  4. SCTR has secretin receptor activity (GO:0015055)
  5. GNAS has G protein activity (GO:0003925)

  6. ADCY6 has adenylate cyclase activity (GO:0004016)

  7. Correct Cellular Locations:

  8. SCT is correctly located in extracellular space (GO:0005615)
  9. SCTR is correctly located in plasma membrane (GO:0005886)

  10. GNAS is correctly located in cytosol (GO:0005829)

  11. Accurate Biological Process: All activities are part of the adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189).

  12. Complete Causal Chain: The model includes appropriate causal relationships using "directly positively regulates" (RO:0002629) between activities:

  13. SCT hormone activity → SCTR receptor activity
  14. SCTR receptor activity → GNAS G protein activity

  15. GNAS G protein activity → ADCY6 adenylate cyclase activity

  16. Appropriate Output: ADCY6 adenylate cyclase activity has the output of 3',5'-cyclic AMP (CHEBI:17489).

Suggestions for Improvement

  1. Evidence Quality: The model uses a mix of evidence types:
  2. Direct assay evidence (ECO:0000314) for most critical relationships
  3. Sequence similarity evidence (ECO:0000250) for some aspects of SCT and SCTR

This is appropriate, but it would be beneficial to ensure the most direct experimental evidence is used when available.

  1. Model Completeness: The model could potentially be expanded to include:
  2. Downstream effects of cAMP production (e.g., PKA activation)
  3. Additional regulatory relationships that may modulate the pathway

  4. Potential cross-talk with other signaling pathways

  5. GNAS Representation: The model uses UniProtKB:Q5JWF2 (GNAS1_HUMAN) for the G protein alpha subunit, which represents the XLas isoform. While this is technically correct as it can couple to SCTR, the more commonly referenced isoform in GPCR signaling literature is P63092 (GNAS2). Both are functional, so this is not incorrect.

Biological Accuracy

  1. Secretin Function: The model correctly represents secretin's role as a hormone that binds to the secretin receptor. According to UniProt data, secretin (SCT) is involved in regulating pH of duodenal content, food intake, and water homeostasis, which aligns with the signaling pathway represented.

  2. Receptor-G Protein Coupling: SCTR is appropriately shown to couple to Gs (GNAS), which is consistent with literature showing that secretin receptor activates adenylyl cyclase through Gs.

  3. Downstream Signaling: The production of cAMP by adenylyl cyclase 6 (ADCY6) as a result of G protein activation is biologically accurate.

Compliance with GO-CAM Best Practices

  1. Signaling Receptor Guidelines: The model follows the guidelines for signaling receptor activity annotation by:
  2. Correctly representing the hormone (ligand) activity with its "directly positively regulates" relationship to the receptor
  3. Properly locating the hormone in extracellular space and the receptor in plasma membrane

  4. Situating all activities within the appropriate biological process

  5. Complex Annotation: The model appropriately annotates individual proteins rather than complexes, which is the recommended approach when the specific protein carrying the activity is known.

  6. Causal Relations: The model correctly uses "directly positively regulates" for the causal chain, which is appropriate for these direct molecular interactions.

Conclusion

The GO-CAM model "Signaling by Secretin/SCT mediated by SCTR receptor (Human)" is a well-constructed representation of the secretin signaling pathway. It follows GO-CAM best practices for signaling pathway annotation and accurately represents the biological process with appropriate molecular functions, cellular locations, and causal relationships.

The model correctly captures the key molecular steps in secretin signaling from hormone-receptor binding through G protein activation to adenylyl cyclase stimulation and cAMP production. The evidence used to support the model is appropriate, with direct experimental evidence cited for most key relationships.

This model provides a valuable resource for understanding secretin signaling and serves as a good template for other GPCR signaling pathways.