Skip to content

Now I'll prepare my review of GO-CAM model 6197061700001643.

GO-CAM Model Review

Review of GO-CAM Model 6197061700001643: Epidermal growth factor receptor signaling pathway 3 (Mouse)

Model Overview

This model (https://bioregistry.io/go.model:6197061700001643) represents the epidermal growth factor receptor (EGFR) signaling pathway in mice, focusing on three key proteins:

  1. Amphiregulin (Areg) - an EGFR ligand that activates the receptor
  2. EGFR (Epidermal Growth Factor Receptor) - a receptor tyrosine kinase
  3. ADAM17 (A Disintegrin And Metalloproteinase 17) - a protease that processes Areg

Model Structure Assessment

The model is generally well-constructed and follows several best practices for GO-CAM modeling. I'll evaluate its structure, completeness, and biological accuracy:

Strengths

  1. Accurate biological pathway representation: The model correctly represents the relationship between ADAM17, Areg, and EGFR in the EGFR signaling pathway.

  2. Proper annotation of molecular functions:

  3. ADAM17 is annotated with metallopeptidase activity (GO:0008237)
  4. Areg is annotated with receptor ligand activity (GO:0048018)

  5. EGFR is annotated with transmembrane receptor protein tyrosine kinase activity (GO:0004714)

  6. Appropriate location annotations:

  7. ADAM17 is located in the plasma membrane (GO:0005886)
  8. Areg is located in the extracellular space (GO:0005615)

  9. EGFR is located in the plasma membrane (GO:0005886)

  10. Proper causal relationships:

  11. ADAM17 positively regulates Areg via the RO:0002304 relation (causally upstream of, positive effect)

  12. Areg positively regulates EGFR via the RO:0002629 relation (directly positively regulates)

  13. Each activity is part of the appropriate biological process:

  14. All activities are part of epidermal growth factor receptor signaling pathway (GO:0007173)

  15. Good evidence support: Multiple evidences with appropriate ECO codes and literature references support the annotations.

Areas for Improvement

  1. Missing details on ADAM17 processing of Areg: While the model shows that ADAM17 has a positive regulatory effect on Areg, it doesn't explicitly represent that ADAM17 cleaves the membrane-bound precursor of Areg to release the soluble form that then binds to EGFR. A more specific process "signaling receptor ligand precursor processing" (GO:0140448) is used for ADAM17, but the model could better clarify this relationship.

  2. Incomplete EGFR downstream signaling: The model doesn't include any downstream effectors of EGFR. Once activated, EGFR typically initiates several signaling cascades including Ras/Raf/MEK/ERK, PI3K/AKT, PLCĪ³, and STAT pathways.

  3. Limited context information: The model doesn't specify the biological context or outcome of this signaling pathway, which could include cell proliferation, differentiation, or survival.

Biological Accuracy Assessment

The model is biologically accurate based on current knowledge about EGFR signaling:

  1. ADAM17 role: ADAM17 (also known as TACE) is indeed a metalloprotease that cleaves and activates several EGFR ligands, including Amphiregulin, as correctly represented in the model. The evidence from PMID:14993236 supports this relationship.

  2. Amphiregulin as an EGFR ligand: Amphiregulin is correctly represented as an EGFR ligand that activates the receptor's tyrosine kinase activity, leading to downstream signaling. The evidence from PMID:23333074 and other references supports this relationship.

  3. EGFR signaling: The model correctly represents EGFR as a transmembrane receptor tyrosine kinase that gets activated upon ligand binding.

Recommendations for Improvement

To enhance this GO-CAM model, I recommend:

  1. Extend downstream signaling: Include key downstream effectors of EGFR, such as GRB2, SOS, RAS, and components of the MAPK pathway.

  2. Add more specificity to ADAM17 processing: Explicitly model that ADAM17 cleaves the membrane-bound precursor of Areg to release the soluble form.

  3. Include biological outcomes: Add associations to biological processes that are outcomes of EGFR signaling, such as cell proliferation, migration, or differentiation.

  4. Consider adding regulation of ADAM17: If relevant literature exists, include information on how ADAM17 activity is regulated in this context.

  5. Add cellular compartment details: While ADAM17 and EGFR are annotated to plasma membrane, more specific locations could be added if supported by evidence.

Conclusion

Model gomodel:6197061700001643 represents a simplified but accurate view of the Amphiregulin-EGFR signaling pathway in mouse. It follows GO-CAM best practices for representing signaling pathways according to the documentation on annotating signaling receptor activity. The model could be expanded to include more detail on downstream signaling and the specific mechanisms of Areg processing by ADAM17, but it provides a solid foundation of this important signaling pathway.