Skip to content

64e7eefa00000854 Tumor necrosis factor mediated signaling pathway 1 Mouse

Now that I've reviewed the model and guidelines, I'll provide a comprehensive review of the GO-CAM model gomodel:64e7eefa00000854 - "Tumor necrosis factor-mediated signaling pathway 1 (Mouse)".

GO-CAM Model Review: Tumor necrosis factor-mediated signaling pathway 1 (Mouse)

Model Summary:

This GO-CAM model (ID: gomodel:64e7eefa00000854) represents the tumor necrosis factor (TNF) signaling pathway in mouse. The model accurately portrays TNF-mediated signaling, starting with TNF ligand binding to its receptor, followed by recruitment of adaptor proteins, and culminating in the activation of the NF-κB pathway. The model includes both the positive regulatory aspects of the pathway and negative regulation elements.

Strengths:

  1. Pathway Completeness: The model provides a comprehensive view of the TNF signaling pathway from receptor binding through downstream effectors.

  2. Evidential Support: Almost all interactions are backed by appropriate experimental evidence, primarily from research papers, with proper ECO codes for the type of evidence.

  3. Molecular Functions: The molecular functions assigned to proteins are appropriate (e.g., TNF has receptor ligand activity, TNFR1 has signaling receptor activity, TRADD has signaling adaptor activity).

  4. Appropriate Causal Relations: The model uses appropriate causal relation predicates between activities (e.g., "directly positively regulates", "provides input for").

  5. Proper Biological Context: Activities are correctly placed in the appropriate biological processes (GO:0043123 - positive regulation of canonical NF-kappaB signal transduction).

Issues and Recommendations:

  1. Missing Evidence: There's one causal association missing evidence:

  2. The causal relation between Rnf31 (MGI:MGI:1934704) E3 ubiquitin ligase activity and Ripk1 (MGI:MGI:108212) signaling adaptor activity lacks evidence. Evidence should be added to support this interaction.

  3. Complexity Annotation:

  4. The NF-kappaB p50/p65 complex (GO:0035525) is appropriately represented as enabling DNA-binding transcription activator activity, consistent with the guidelines for complex annotation.

  5. E3 Ubiquitin Ligase Representation:

  6. The LUBAC complex components are represented individually rather than as a complex, which is appropriate according to guidelines when the individual activities of each component are known.

  7. Rbck1 (MGI:MGI:1344372) with ubiquitin ligase activator activity, Sharpin (MGI:MGI:1913331) with protein-macromolecule adaptor activity, and Rnf31 (MGI:MGI:1934704) with E3 ubiquitin ligase activity are all correctly annotated according to the E3 ubiquitin ligase guidelines.

  8. BP Context Consistency:

  9. Most activities are part of "positive regulation of canonical NF-kappaB signal transduction" (GO:0043123), which is appropriate.
  10. However, some ubiquitination-related activities are correctly placed in "protein polyubiquitination" (GO:0000209), providing appropriate context for these activities.

  11. Nfkbia (MGI:MGI:104741) is correctly placed in "negative regulation of canonical NF-kappaB signal transduction" (GO:0043124).

  12. Receptor Activity Annotation:

  13. The TNF receptor (Tnfrsf1a) and ligand (Tnf) interactions follow the guidelines for protein ligand-activated signaling receptor annotation.

  14. The relationship between ligand and receptor activity uses "directly positively regulates" as recommended.

  15. Signaling Adaptors Representation:

  16. The model includes multiple signaling adaptors (TRADD, TRAF2, RIP1) which are correctly annotated with "signaling adaptor activity" (GO:0035591).
  17. The causal relationships between these adaptors follow appropriate chain of activation as described in literature.

Technical Review:

According to GO-CAM guidelines: 1. Complex annotation: Correctly implemented for the NF-κB complex. 2. Molecular adaptors: Properly annotated with appropriate inputs and causal relations. 3. E3 ubiquitin ligases: Correctly represented with proper functions and relations. 4. Signaling receptor activity: TNF and TNFR1 interaction follows prescribed guidelines. 5. Causal relations: Uses appropriate causal relations for regulatory relationships.

Biological Content Consistency:

The model accurately represents the TNF signaling pathway as described in the literature. The referenced articles (especially PMID:18641653) support the role of TRADD as a critical adaptor in TNF signaling that orchestrates the formation of TNFR1 signaling complexes, which is reflected in the model.

The inclusion of negative regulation by Nfkbia (IκBα) provides appropriate regulatory balance to the pathway.

Recommendations for Improvement:

  1. Add evidence for the missing causal relation between Rnf31 and Ripk1.

  2. Consider adding more detailed information about the NF-κB-mediated transcriptional response, which could extend the model beyond signaling activation.

  3. The current model focuses on the canonical NF-κB activation pathway. Consider adding elements of the non-canonical pathway if relevant.

Conclusion:

Overall, this is a well-constructed GO-CAM model that accurately represents the TNF signaling pathway leading to NF-κB activation in mouse. It follows GO-CAM best practices for annotation of complexes, signaling receptors, E3 ubiquitin ligases, and adaptors. The model is parsimonious and provides a clear representation of the pathway that would be understandable to researchers familiar with signaling pathways.

The model is suitable for release with only minor updates recommended, primarily adding the missing evidence for one causal relation.