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61b2b68300000203 ERBB2 ERBB4 signaling pathway 3 Mouse

Based on the information I've gathered, I'll now review the GO-CAM model gomodel:61b2b68300000203 "ERBB2-ERBB4 signaling pathway 3 (Mouse)".

GO-CAM Review: gomodel:61b2b68300000203

Model Overview

This model represents the ERBB2-ERBB4 signaling pathway in mouse (NCBITaxon:10090), focusing on neuregulin-1 (Nrg1) signaling through ERBB receptors. The model describes a molecular pathway that involves:

  1. Metallopeptidase and endopeptidase activities (ADAM10, ADAM17, BACE1) that process the NRG1 precursor
  2. The resulting NRG1 ligand that activates ERBB receptors
  3. The receptor activity of ERBB4 binding to NRG1
  4. Downstream ERBB2 protein tyrosine kinase activity

Biological Accuracy Assessment

The biological content of this model is well-supported by the literature:

  1. NRG1 processing by proteases: The model correctly shows that BACE1 (MGI:MGI:1346542), ADAM10 (MGI:MGI:109548), and ADAM17 (MGI:MGI:1096335) process NRG1 through their metallopeptidase/endopeptidase activities (ref: PMID:17099708). This cleavage is required to release the active form of NRG1 that can signal to ERBB receptors.

  2. NRG1 signaling through ERBB receptors: The model correctly shows that cleaved NRG1 (MGI:MGI:96083) acts as a receptor ligand (GO:0048018) that activates the ERBB4 receptor (MGI:MGI:104771) through its neuregulin receptor activity (GO:0038131). This interaction is supported by PMID:19632177, which describes NRG1/ErbB4 signaling.

  3. ERBB2-ERBB4 heterodimerization: The model represents ERBB2 (MGI:MGI:95410) with protein tyrosine kinase activity (GO:0004713) downstream of ERBB4 activation, which is consistent with the literature. PMID:19632177 describes how "Binding of NRG1 to ErbB4 increases its kinase activity and leads to heterodimerization with ErbB2 or homodimerization with ErbB4."

Modeling Best Practices Assessment

The model follows GO-CAM best practices in several ways:

  1. Appropriate use of causal relationships: The model uses RO:0002304 (causally upstream of, positive effect) to connect the protease activities to NRG1 ligand activity, and RO:0002629 (directly positively regulates) to connect NRG1 to ERBB4 and ERBB4 to ERBB2, which properly represents the direction of signaling.

  2. Proper representation of cellular components: The activities are correctly annotated with cellular locations. The proteases (BACE1, ADAM10, ADAM17) and receptors (ERBB2, ERBB4) are located at the plasma membrane (GO:0005886), while the processed NRG1 is in the extracellular space (GO:0005615).

  3. Proper complex representation: The model appropriately handles the ERBB2-ERBB4 complex by showing the individual activities of each protein rather than using a complex GO term. This follows the recommendation in the "How to annotate complexes in GO-CAM" document for cases where the activities of the individual components are known.

Areas for Improvement

While the model is generally well-constructed, I identified a few minor areas for improvement:

  1. Evidence for ERBB2 activity: The evidence for ERBB2 protein tyrosine kinase activity comes from PMID:8702723, for which the full text was not available. It would be helpful to verify this with additional evidence if possible.

  2. Lack of downstream effects: The model shows ERBB2 tyrosine kinase activity but doesn't include any downstream targets of this activity. Based on PMID:19632177, the NRG1/ERBB4/ERBB2 signaling activates the PI3K-Akt pathway. Including these downstream components would make the model more complete.

  3. Biological process annotation: All activities are correctly annotated with "part_of" the ERBB2-ERBB4 signaling pathway (GO:0038135), but the three proteases (BACE1, ADAM10, and ADAM17) are also annotated with "signaling receptor ligand precursor processing" (GO:0140448). While technically correct, it might be clearer to be more specific about their role in NRG1 processing specifically.

Conclusion

The GO-CAM model gomodel:61b2b68300000203 is a high-quality representation of the ERBB2-ERBB4 signaling pathway in mouse that correctly captures the processing of NRG1 by proteases and its signaling through ERBB receptors. The model is biologically accurate, supported by published literature, and follows GO-CAM best practices for representing molecular activities and their causal relationships.

The model could be extended to include downstream effects of ERBB2 kinase activity, such as PI3K-Akt pathway activation, which would provide a more complete picture of the signaling cascade. Overall, this model provides a valuable representation of NRG1-ERBB signaling that is consistent with current biological knowledge.