Skip to content

Based on my research, I can now provide a comprehensive review of GO-CAM model: gomodel:60ad85f700000309 titled "Notch signaling pathway via N-Dl (D.mel)".

GO-CAM Review: Notch signaling pathway via N-Dl (D.mel)

Model Overview

This model represents the Notch signaling pathway in Drosophila melanogaster, focusing on the interaction between the Notch receptor (N) and its ligand Delta (Dl), and the downstream effects of this signaling pathway.

Components and Activities

The model consists of 5 key activities:

  1. Delta (Dl) - FB:FBgn0000463
  2. Molecular Function: receptor ligand activity (GO:0048018)
  3. Located in: membrane (GO:0016020)
  4. Part of: Notch signaling pathway (GO:0007219)

  5. Directly positively regulates Notch transmembrane signaling receptor activity

  6. Notch (N) - FB:FBgn0004647

  7. Molecular Function: transmembrane signaling receptor activity (GO:0004888)
  8. Located in: plasma membrane (GO:0005886)
  9. Part of: Notch signaling pathway (GO:0007219)

  10. Directly positively regulates Kuzbanian metalloendopeptidase activity

  11. Kuzbanian (kuz) - FB:FBgn0259984

  12. Molecular Function: metalloendopeptidase activity (GO:0004222)
  13. Located in: cellular_component (GO:0005575)
  14. Part of: Notch signaling pathway (GO:0007219)

  15. Directly positively regulates Presenilin endopeptidase activity

  16. Presenilin (Psn) - FB:FBgn0284421

  17. Molecular Function: endopeptidase activity (GO:0004175)
  18. Located in: cell surface (GO:0009986)
  19. Part of: Notch signaling pathway (GO:0007219)

  20. Directly positively regulates Notch transcription coactivator activity

  21. Notch (N) - FB:FBgn0004647

  22. Molecular Function: transcription coactivator activity (GO:0003713)
  23. Located in: nucleus (GO:0005634)
  24. Part of: Notch signaling pathway (GO:0007219)

Evaluation of Model Quality

Adherence to GO-CAM Best Practices

  1. Signaling Receptor Activity Annotations
  2. The model correctly represents the interaction between Delta (ligand) and Notch (receptor) following the guidelines for protein ligand-activated signaling receptors.
  3. The ligand (Delta) correctly has "receptor ligand activity" (GO:0048018) as its molecular function.
  4. Delta is appropriately located in the membrane.
  5. The causal relation between Delta activity and Notch receptor activity is correctly labeled as "directly positively regulates" (RO:0002629).

  6. Notch receptor correctly has "transmembrane signaling receptor activity" (GO:0004888) as its molecular function and is located in the plasma membrane.

  7. Pathway Flow and Logic

  8. The model captures the sequential events in Notch signaling:
    1. Delta binds to Notch receptor
    2. Notch is cleaved by Kuzbanian (S2 cleavage)
    3. Notch is further cleaved by Presenilin (S3 cleavage)
    4. The Notch intracellular domain (NICD) translocates to the nucleus and acts as a transcription coactivator

  9. All steps are properly connected with the appropriate causal relation "directly positively regulates" (RO:0002629).

  10. Transcription Coactivator Activity

  11. The nuclear activity of Notch as a transcription coactivator (GO:0003713) is properly represented, following the guidelines for transcription coregulator activity.
  12. It is correctly located in the nucleus (GO:0005634).

Accuracy of Biological Content

The model accurately represents the Notch signaling pathway in Drosophila melanogaster as supported by the literature:

  • From the PMID:15611340 paper, we can confirm the pathway logic: Delta binds to Notch, triggering a series of proteolytic cleavages first by Kuzbanian (S2 cleavage) and then by Presenilin (S3 cleavage), which releases the Notch intracellular domain (Nintra) that translocates to the nucleus to act as a transcriptional coactivator with Suppressor of Hairless (SuH).

  • The model correctly captures the membrane location of Delta and Notch, and the sequential proteolytic cleavages that lead to Notch activation.

  • The UniProt entries confirm that Delta is a ligand for the Notch receptor, and that cleaved Notch acts as a transcriptional activator complex in the nucleus.

Areas for Improvement

  1. Missing Components:
  2. The model does not include Suppressor of Hairless (SuH), which forms a complex with the Notch intracellular domain in the nucleus to regulate transcription as mentioned in the literature.

  3. Specific target genes of Notch signaling, such as the Enhancer of split Complex (E(spl)C) genes mentioned in PMID:15611340, are not included.

  4. Incomplete Annotations:

  5. Kuzbanian's cellular location is annotated as the generic "cellular_component" (GO:0005575) rather than a more specific cellular location.

  6. The model could benefit from including evidence for some of the associations.

  7. Molecular Details:

  8. The model could more explicitly represent the cleavage of Notch and the release of the Notch intracellular domain (NICD) that translocates to the nucleus.
  9. The interaction with glycosylation enzymes like O-fut1 and fringe, which modify Notch's ability to bind Delta (as mentioned in the UniProt entry for Delta), is not represented.

Conclusion

The GO-CAM model gomodel:60ad85f700000309 provides a good representation of the core Notch signaling pathway in Drosophila melanogaster. It correctly captures the sequential events from ligand binding to transcriptional regulation and follows most GO-CAM best practices.

The model could be enhanced by: 1. Including Suppressor of Hairless and target genes 2. Providing more specific cellular location for Kuzbanian 3. Adding molecular details about Notch cleavage and NICD translocation 4. Representing modifiers of Notch-Delta interactions such as O-fut1 and fringe

Overall, this model serves as a solid representation of the Notch signaling pathway and could be a useful reference model for further annotation of Notch signaling in other contexts.