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6197061700002226 ERBB2 ERBB4 signaling pathway 2 Mouse

Now that I have gathered detailed information about the model and its components, let me review the GO-CAM model 6197061700002226 "ERBB2-ERBB4 signaling pathway 2 (Mouse)".

GO-CAM Model Review: ERBB2-ERBB4 signaling pathway 2 (Mouse)

Model Overview

The model (gomodel:6197061700002226) represents the ERBB2-ERBB4 signaling pathway in mouse, focusing on the interactions between: 1. Epiregulin (Ereg) as a receptor ligand 2. ERBB4 (transmembrane receptor tyrosine kinase) 3. ERBB2 (receptor tyrosine-protein kinase) 4. ADAM17 (disintegrin and metalloproteinase 17) as a metallopeptidase involved in ligand processing

Model Structure Analysis

Activity Flow

The activity flow in this model follows this pathway: 1. ADAM17 (MGI:MGI:1096335) with metallopeptidase activity (GO:0008237) positively regulates (RO:0002304) Ereg activity 2. Ereg (MGI:MGI:107508) with receptor ligand activity (GO:0048018) directly positively regulates (RO:0002629) ERBB4 activity 3. ERBB4 (MGI:MGI:104771) with transmembrane receptor protein tyrosine kinase activity (GO:0004714) directly positively regulates (RO:0002629) ERBB2 activity 4. ERBB2 (MGI:MGI:95410) with protein tyrosine kinase activity (GO:0004713)

All these activities contribute to the ERBB2-ERBB4 signaling pathway (GO:0038135).

Cellular Locations

  • ADAM17: plasma membrane (GO:0005886)
  • Ereg: extracellular space (GO:0005615)
  • ERBB4: plasma membrane (GO:0005886)
  • ERBB2: plasma membrane (GO:0005886)

Evidence Assessment

The model is supported by evidence from experimental literature: - PMID:9556621 is cited as evidence for Ereg's receptor ligand activity, its regulation of ERBB4, and ERBB4's regulation of ERBB2 - PMID:14993236 supports the role of ADAM17 in processing signaling receptor ligand precursors

Strengths of the Model

  1. Consistency with Receptor Signaling Guidelines: The model follows the GO-CAM guidelines for signaling receptor activity by correctly showing:
  2. A ligand (Ereg) with receptor ligand activity in the extracellular space
  3. The causal relation "directly positively regulates" between the ligand and receptor
  4. The receptor (ERBB4) with appropriate tyrosine kinase activity

  5. Downstream signaling to ERBB2

  6. Correct Representation of Ligand Processing: The model includes ADAM17's role in metallopeptidase activity, which correctly represents its biological function in processing receptor ligand precursors (including Ereg).

  7. Biological Accuracy: The interactions between Ereg, ERBB4, and ERBB2 align with known biology - Ereg can activate ERBB4, which forms heterodimers with ERBB2 to initiate downstream signaling.

  8. Appropriate Cellular Locations: The cellular locations for each protein are correctly annotated.

Issues/Concerns with the Model

  1. Missing Downstream Signaling Components: The model doesn't include downstream effectors beyond ERBB2. The signaling cascade typically continues to activate pathways like MAPK and PI3K/AKT.

  2. ERBB2 Activity Endpoint: While ERBB2 is shown with protein tyrosine kinase activity, there's no indication of what targets it phosphorylates, leaving the pathway incomplete.

  3. Heterodimer Representation: Although ERBB4 is shown to regulate ERBB2, the model doesn't explicitly capture that they form a heterodimer complex. According to the "How to annotate complexes in GO-CAM" document, it might be more accurate to represent the heterodimer if the activities are shared.

  4. Evidence Details: While PMID:9556621 is cited, we couldn't retrieve its full text to fully evaluate the evidence quality.

Recommendations for Improvement

  1. Complete the Signaling Pathway: Add downstream effectors of ERBB2 signaling (e.g., SHC, GRB2, MAPK) to provide a more complete view of the pathway.

  2. Consider Representing the ERBB2/ERBB4 Heterodimer: If the receptor functions as a heterodimer, consider representing this according to complex annotation guidelines, especially if both proteins contribute to the signaling activity.

  3. Add More Evidence: Include additional supporting literature to strengthen the evidence base, particularly for the role of ADAM17 in Ereg processing.

  4. Add Specific Targets for ERBB2: Indicate the specific substrates that ERBB2 phosphorylates to complete the signaling cascade.

Conclusion

This model provides a good basic representation of the initial steps in ERBB2-ERBB4 signaling in response to Ereg stimulation. It correctly captures the receptor-ligand interaction and the sequential activation of ERBB4 and ERBB2. The inclusion of ADAM17's role in ligand processing adds valuable context.

However, the model would benefit from extending the signaling cascade to include downstream effectors and targets of ERBB2 kinase activity. Also, more explicit representation of the ERBB2-ERBB4 heterodimer formation would better align with the biology of this pathway.

Overall, the model is biologically accurate but somewhat limited in scope, providing a foundation that could be expanded to show the complete signaling pathway.