Skip to content

Based on my analysis of the GO-CAM model and relevant literature, I'll now provide a comprehensive review of the GO-CAM model gomodel:6516135700000211.

Review of GO-CAM Model: Tumor necrosis factor-mediated signaling pathway 2 (Mouse)

Model ID: gomodel:6516135700000211

Overview

This model represents the tumor necrosis factor (TNF)-mediated signaling pathway in mouse. It includes a sequential series of activities starting with TNF cytokine activity, leading through TNF receptor signaling, adapter proteins, and culminating in sphingomyelin phosphodiesterase activity.

Structure and Content

The model contains six activities with the following key genes/proteins: 1. TNF (MGI:MGI:104798) - cytokine activity 2. TNFRSF1A (MGI:MGI:1314884) - tumor necrosis factor receptor activity 3. NSMAF (MGI:MGI:1341864) - signaling adaptor activity 4. RACK1 (MGI:MGI:101849) - signaling adaptor activity 5. EED (MGI:MGI:95286) - enzyme activator activity 6. SMPD2 (MGI:MGI:1278330) - sphingomyelin phosphodiesterase activity

The causal flow is: TNF → TNFRSF1A → NSMAF → RACK1 → EED → SMPD2, with all regulatory relationships being "directly positively regulates" (RO:0002629).

Strengths

  1. Appropriate pathway representation: The model correctly represents the TNF signaling pathway leading to neutral sphingomyelinase activation, which is supported by the literature (PMIDs 14985352, 12391233, 9520418).

  2. Correct molecular function annotations: The molecular functions are appropriately assigned, such as cytokine activity for TNF and receptor activity for TNFRSF1A.

  3. Proper cellular context: Activities are correctly localized, with TNF in extracellular space (GO:0005615) and the receptor/signaling components at the plasma membrane (GO:0005886).

  4. Consistent causal relationships: The use of "directly positively regulates" (RO:0002629) is appropriate for the signaling cascade represented.

  5. Evidence support: Each activity and relationship is supported by experimental evidence, primarily from the literature.

Issues/Concerns

  1. Missing supporting annotation for causal relationship: The causal association between NSMAF (gomodel:6516135700000211/6516135700000222) and RACK1 (gomodel:6516135700000211/6516135700000221) lacks evidence annotations, which should be included.

  2. Activity annotation considerations: Based on the PMID:9520418 paper, SMPD2 (neutral sphingomyelinase) is an important enzyme in sphingolipid signaling. While the model correctly represents its activity, the literature suggests that TNF only moderately increases ceramide production through this pathway, which is consistent with the model but could be mentioned in annotations.

  3. Biological process annotation: All activities except SMPD2 are annotated as part of "tumor necrosis factor-mediated signaling pathway" (GO:0033209), while SMPD2 is annotated to "ceramide metabolic process" (GO:0006672). It might be worth considering whether SMPD2 should also be linked to the TNF signaling pathway, since it appears to be the endpoint of this particular signaling cascade.

  4. Complex considerations: According to the "How to annotate complexes in GO-CAM" document, if specific subunits carrying activities are known, they should be represented individually. This model correctly follows this approach by representing individual proteins rather than complexes.

Adherence to GO-CAM Best Practices

  1. The model follows the signaling receptor annotation guidelines appropriately by having:
  2. The cytokine (TNF) with cytokine activity in extracellular space
  3. The receptor (TNFRSF1A) with receptor activity at the plasma membrane

  4. The correct causal relationships between the components

  5. The model is parsimonious and represents a clear flow of activities without unnecessary complexity.

  6. All annotations are supported by experimental evidence, mostly using ECO:0000314 (direct assay evidence) and ECO:0000266 (sequence orthology evidence).

Recommendations

  1. Add missing evidence: Provide evidence annotations for the causal association between NSMAF and RACK1.

  2. Consider biological process annotation for SMPD2: Evaluate whether SMPD2 should also be annotated to the TNF signaling pathway in addition to ceramide metabolism.

  3. Review literature completeness: Based on PMID:9520418, the model accurately represents the pathway, but annotations could reflect that the effect of TNF on SMPD2 activation is moderate rather than strong.

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the TNF signaling pathway leading to neutral sphingomyelinase activation in mouse. The model follows GO-CAM best practices and is supported by appropriate evidence. With minor additions of missing evidence annotations, this model provides a valuable representation of this signaling pathway.