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663d668500001492 TRAIL TRAILR2 interaction leading to apoptosis

Based on my review of the GO-CAM model "gomodel:663d668500001492" titled "TRAIL/TRAILR2 interaction leading to apoptosis", I can provide a comprehensive assessment of the model from the perspective of a GO-CAM curator.

Summary of the Model

This model represents the signaling pathway initiated by the interaction between TRAIL (TNF-related apoptosis-inducing ligand, UniProtKB:P50591) and its receptor TRAIL-R2 (TNFRSF10B, UniProtKB:O14763), leading to apoptosis through a cascade of molecular events. The model includes:

  1. TRAIL cytokine activity in the extracellular space
  2. TRAIL-R2 signaling receptor activity at the plasma membrane
  3. A cascade of adaptor proteins (TRADD, FADD) in the cytoplasm
  4. Activation of caspase-8, an effector protease that mediates apoptosis

Technical Assessment

GO-CAM Structure and Connectivity

The model properly represents a causal chain of molecular activities with appropriate causal relationships (RO:0002629, "directly positively regulates") between: - TRAIL (cytokine activity) → TRAIL-R2 (signaling receptor activity) - TRAIL-R2 → TRADD (protein-macromolecule adaptor activity) - TRADD → FADD (protein-macromolecule adaptor activity) - FADD → caspase-8 (cysteine-type endopeptidase activity)

Evidence Quality

Each activity and causal relationship is supported by experimental evidence with appropriate ECO codes and literature references. The model uses: - ECO:0000314 (direct assay evidence used in manual assertion) - ECO:0000303 (author statement without traceable support) - ECO:0000315 (mutant phenotype evidence)

References include key papers on TRAIL signaling, with primary citations.

Biological Accuracy Assessment

Molecular Functions

The molecular functions assigned to each protein in the model are accurate: - TRAIL (P50591): GO:0005125 (cytokine activity) - This is correct as TRAIL is a cytokine that binds to death receptors. - TRAIL-R2 (O14763): GO:0038023 (signaling receptor activity) - This is appropriate as TRAIL-R2 is a transmembrane receptor that initiates apoptotic signaling. - TRADD (Q15628): GO:0030674 (protein-macromolecule adaptor activity) - TRADD is indeed an adaptor protein that connects TRAIL-R2 to downstream signaling components. - FADD (Q13158): GO:0030674 (protein-macromolecule adaptor activity) - FADD acts as an adaptor that recruits caspase-8. - Caspase-8 (Q14790): GO:0004197 (cysteine-type endopeptidase activity) - This is the correct enzymatic activity of caspase-8.

Subcellular Locations

The locations specified for each activity are biologically accurate: - TRAIL activity occurs in GO:0005615 (extracellular space) - TRAIL-R2 is located at GO:0005886 (plasma membrane) - TRADD, FADD, and caspase-8 activities occur in GO:0005737 (cytoplasm)

Biological Process Context

All activities are properly associated with GO:0036462 (TRAIL-activated apoptotic signaling pathway), which is the correct biological process term for this pathway.

Comparison with Best Practices

According to the "How to annotate complexes in GO-CAM" document, the model appropriately represents individual protein activities rather than complex entities. Each protein is annotated with its specific molecular function, and the causal relationships between activities form a coherent signaling cascade.

Missing Elements or Potential Improvements

While the model is well-constructed, I've identified a few aspects that could be improved or expanded:

  1. Mechanism of FADD-Caspase-8 Interaction: The model shows FADD directly activating caspase-8, but it could more explicitly represent the formation of the death-inducing signaling complex (DISC). The literature (PMID:16762833) indicates that FADD recruits caspase-8 through homotypic death effector domain (DED) interactions.

  2. Caspase-8 Activation Details: The model could include the self-cleavage and dimerization of caspase-8 that is required for its activation. This is an important regulatory step in the pathway.

  3. Downstream Apoptotic Execution: The model could be extended to include downstream targets of caspase-8, such as effector caspases (caspase-3, caspase-7) or BID, which links the extrinsic and intrinsic apoptotic pathways.

  4. Regulatory Influences: The model doesn't represent negative regulators of this pathway, such as FLIP (CFLAR), which can compete with caspase-8 for binding to FADD.

Evidence Assessment

The evidence used in the model is appropriate and comes from reliable sources. The model integrates information from multiple papers that have characterized different aspects of the TRAIL signaling pathway. The papers cited (PMID:21146232, PMID:9485194, etc.) are relevant to the interactions represented.

Recommendations

I would recommend the following enhancements to improve this model:

  1. Include the intermediate step of DISC formation between receptor activation and caspase-8 recruitment.

  2. Add the self-processing and oligomerization of caspase-8 as a regulatory step.

  3. Extend the model to include at least one downstream effector of caspase-8 (e.g., caspase-3 activation).

  4. Consider adding regulatory elements such as FLIP or IAPs that modulate the pathway.

  5. Include cross-talk with the intrinsic apoptotic pathway through the caspase-8-mediated cleavage of BID.

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the core components of the TRAIL/TRAIL-R2 apoptotic signaling pathway. The model follows GO-CAM best practices by representing individual molecular activities and their causal relationships, supported by appropriate evidence. The suggested improvements would enhance the biological completeness of the model but are not critical deficiencies. This model provides a useful representation of TRAIL-induced apoptotic signaling for the GO-CAM knowledge base.