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Now I have enough information to provide a comprehensive review of the GO-CAM model gomodel:617b481400000995.

Review of GO-CAM Model: gomodel:617b481400000995

Model Overview

Title: Epidermal growth factor receptor signaling pathway 1 (Mouse)
Taxon: Mouse (NCBITaxon:10090)
Status: Production
Source: R-HSA-177929

Summary of Model Content

This GO-CAM model represents the epidermal growth factor receptor (EGFR) signaling pathway in mouse. The model contains 4 activities involving:

  1. Metallopeptidase activity (GO:0008237) of Mep1a (MGI:MGI:96963)
  2. Metallopeptidase activity (GO:0008237) of Adam10 (MGI:MGI:109548)
  3. Receptor ligand activity (GO:0048018) of Egf (MGI:MGI:95290)
  4. Epidermal growth factor receptor activity (GO:0005006) of Egfr (MGI:MGI:95294)

The pathway captures the maturation of EGF ligand by metallopeptidases (Mep1a and Adam10), which then activates the EGF receptor (Egfr).

Assessment of Model Structure

The model correctly follows the GO-CAM representation of a receptor-ligand signaling pathway according to guidelines:

  1. Proper causal relations:
  2. Metallopeptidases (Mep1a and Adam10) properly connect to EGF with RO:0002304 (causally upstream of, positive effect)

  3. EGF properly connects to EGFR with RO:0002629 (directly positively regulates)

  4. Appropriate cellular context:

  5. Metallopeptidases and EGFR occur in plasma membrane (GO:0005886)

  6. EGF occurs in extracellular space (GO:0005615)

  7. Proper biological process context:

  8. Metallopeptidases are part of EGF receptor ligand maturation (GO:0038004)
  9. EGFR and EGF are part of EGFR signaling pathway (GO:0007173)

Evidence Assessment

The model uses several sources of evidence:

  1. Experimental Evidence:
  2. ECO:0000314 (direct assay evidence used in manual assertion)
  3. ECO:0000315 (mutant phenotype evidence used in manual assertion)

  4. ECO:0000266 (sequence orthology evidence used in manual assertion)

  5. Literature Support:

  6. PMID:22923609 - Shows Meprin α can shed EGF, activate EGFR pathway
  7. PMID:6248866 - Early study showing EGF-receptor binding in embryonic tissues
  8. PMID:7752576
  9. PMID:17079736
  10. PMID:14993236
  11. PMID:28494873

The evidence from PMID:22923609 strongly supports the role of meprin α (Mep1a) in the shedding of EGF and TGF-α, leading to EGFR activation. This paper demonstrates that meprin α directly cleaves EGF precursors, resulting in EGFR pathway activation.

Biological Accuracy Assessment

The model accurately represents the current understanding of the EGFR signaling pathway:

  1. Role of Metallopeptidases: The inclusion of metallopeptidases (Mep1a and Adam10) in EGF ligand maturation is well-supported by the evidence. From PMID:22923609, we learn that Meprin α can shed EGF from the plasma membrane, contributing to EGFR activation.

  2. EGFR Signaling: The pathway correctly shows how mature EGF activates EGFR through direct positive regulation.

  3. Cellular Locations: The cellular locations of components are biologically accurate, with the receptor and metallopeptidases at the plasma membrane and the ligand in extracellular space.

Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices for signaling receptor pathways:

  1. Ligand Representation: EGF is correctly annotated with receptor ligand activity (GO:0048018) in extracellular space.

  2. Receptor Representation: EGFR is correctly annotated with EGF receptor activity (GO:0005006) at the plasma membrane.

  3. Causal Relations: The model uses appropriate causal relations:

  4. Metallopeptidases → EGF: causally upstream of, positive effect

  5. EGF → EGFR: directly positively regulates

  6. Process Context: All activities are placed in the appropriate biological process context.

Potential Improvements

While the model is structurally sound and biologically accurate, I would suggest the following improvements:

  1. Downstream Signaling: The model could be expanded to include downstream effectors of EGFR activation, such as the RAS-MAPK pathway and PI3K-AKT pathway, which are well-established components of EGFR signaling.

  2. Regulation Mechanisms: Addition of negative regulators of the pathway, such as phosphatases that dephosphorylate EGFR, would provide a more complete picture of pathway regulation.

  3. Feedback Loops: Including feedback mechanisms that downregulate receptor signaling would enhance the model's completeness.

Conclusion

The GO-CAM model gomodel:617b481400000995 is a well-constructed representation of the epidermal growth factor receptor signaling pathway in mouse. It accurately captures the roles of metallopeptidases in EGF ligand maturation and the subsequent activation of EGFR. The model follows GO-CAM best practices for representing receptor-ligand signaling pathways and is supported by appropriate experimental evidence. While it could be expanded to include more downstream components and regulatory mechanisms, the current model provides a solid foundation for understanding the initial steps of EGFR signaling.