Skip to content

Based on my review of the GO-CAM model and the supporting literature, I'll now provide a comprehensive review of the model.

Review of GO-CAM Model: 64c3044100000125

Model Overview

The model titled "Positive regulation of acetylcholine receptor transcription (Mouse)" (https://bioregistry.io/go.model:64c3044100000125) describes a signaling pathway in mouse muscle cells where Neuregulin-1 (NRG1) stimulates the transcription of acetylcholine receptor (AChR) genes through a MAP kinase cascade, ultimately leading to GABPA-mediated transcriptional activation. This pathway is important for neuromuscular junction development and synaptic function.

Model Strengths

  1. Strong Evidential Support: The model is well-supported by multiple research papers (e.g., PMID:11318655, PMID:8702681) that provide experimental evidence for the pathway connections. The citations are used appropriately for each connection in the model.

  2. Correct Use of Molecular Functions: The molecular functions assigned to each gene product (e.g., receptor ligand activity for NRG1, protein tyrosine kinase activity for ErbB2/3, etc.) are appropriate based on the scientific literature.

  3. Clear Pathway Flow: The model presents a coherent signaling cascade from NRG1 binding to receptors through MAP kinase activation to transcriptional activation of AChR genes, which aligns with established literature.

  4. Appropriate Causal Connections: The model correctly uses the RO:0002629 ("directly positively regulates") predicate for causal relationships between activities in the pathway.

Areas for Improvement

  1. Missing Evidence for Some Causal Associations: Some causal connections (between RAF1 and MAP2K1/MAP2K4) lack explicit evidence annotations. All causal associations should include supporting evidence.

  2. Cellular Component Annotations: While some activities in the model have appropriate cellular component annotations (e.g., postsynaptic membrane for receptor activities), some intermediate steps in the pathway would benefit from more specific cellular localization.

  3. Model Completeness: The model could potentially benefit from including:

  4. The downstream effects of CHRNE (acetylcholine receptor subunit epsilon) activation
  5. A more explicit representation of how JNK cascade activation leads to MAPK8 activity

Scientific Accuracy

The model accurately represents the current scientific understanding of NRG1-induced AChR transcription as described in the primary literature. Key highlights of the pathway include:

  1. NRG1 Signaling Initiation: The model correctly shows NRG1 (Mmus) activating neuregulin receptor activity of ErbB3, which occurs in the extracellular space.

  2. Receptor Tyrosine Kinase Activation: The model shows ErbB2 tyrosine kinase activation downstream of ErbB3, which is consistent with the literature showing ErbB2/ErbB3 heterodimerization.

  3. MAPK Cascade: The model accurately depicts the three-tier kinase cascade (RAF1 → MAP2K1/MAP2K4 → MAPK8) that is activated following receptor stimulation.

  4. Transcription Factor Activation: The model correctly shows MAPK8-mediated activation of GABPA, which then activates transcription of the acetylcholine receptor gene (CHRNE), as supported by PMID:11318655, which demonstrated that NRG1-induced phosphorylation of GABPA at threonine 280 contributes to AChR gene transcription.

GO-CAM Best Practices Assessment

The model generally follows GO-CAM best practices, particularly:

  1. Activity Connections: Activities are connected using appropriate predicates that reflect the biological relationships.

  2. Evidence Documentation: Most activities and connections are supported by appropriate evidence codes and literature references.

  3. Complex Representation: The model appropriately represents protein complexes by focusing on the specific activities of individual subunits rather than using complex terms, which is consistent with GO-CAM best practices.

Specific Recommendations

  1. Add evidence annotations to the causal associations between RAF1 (MGI:97847) and MAP2K1/MAP2K4, preferably from the cited literature.

  2. Consider adding cellular component annotations for the MAP kinase cascade components to better represent their subcellular localization.

  3. Consider adding information about the biological outcome of acetylcholine receptor activity in the context of neuromuscular junction function.

Overall Assessment

This GO-CAM model presents a scientifically accurate representation of the NRG1-induced signaling pathway leading to acetylcholine receptor transcription in mouse muscle cells. The model is well-supported by experimental evidence and follows GO-CAM best practices. With minor enhancements as suggested above, the model would provide an even more comprehensive representation of this important signaling pathway.