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Based on my review of the GO-CAM model and its components, I'll now provide a comprehensive assessment of the model and identify any potential issues or areas for improvement.

GO-CAM Model Review: gomodel:663d668500003144

Model Overview

Title: TGFB1-mediated signaling pathway (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production
Model ID: gomodel:663d668500003144

This GO-CAM represents the TGF-beta1 signaling pathway in humans, showing the interactions between the cytokine TGFB1, the receptors TGFBR1 and TGFBR2, and the downstream effector SMAD2.

Model Components

The model consists of 4 main activities:

  1. TGFB1 (P01137) with cytokine activity (GO:0005125) in extracellular space (GO:0005615)
  2. TGFBR2 (P37173) with TGF-beta receptor type II activity (GO:0005026) at plasma membrane (GO:0005886)
  3. TGFBR1 (P36897) with TGF-beta receptor type I activity (GO:0005025) at plasma membrane (GO:0005886)
  4. SMAD2 (Q15796) with DNA-binding transcription factor activity (GO:0003700) in nucleus (GO:0005634)

Causal Relationships

The model represents the following causal chain: - TGFB1 directly positively regulates (RO:0002629) TGFBR2 - TGFBR2 directly positively regulates (RO:0002629) TGFBR1 - TGFBR1 directly positively regulates (RO:0002629) SMAD2

All activities are part of the GO:0007179 (transforming growth factor beta receptor signaling pathway).

Strengths

  1. Biological Accuracy: The model correctly captures the canonical TGF-beta signaling pathway where the cytokine TGFB1 binds to TGFBR2, which then recruits and phosphorylates TGFBR1, leading to the activation of SMAD2.

  2. Evidence Support: Each component has appropriate evidence codes and PMID references supporting the annotations.

  3. Cellular Localization: Appropriate cellular compartments are assigned to each protein, reflecting their known localizations.

Areas for Improvement

  1. SMAD2 Transcription Factor Activity:
  2. The model uses the general term "DNA-binding transcription factor activity" (GO:0003700) for SMAD2. According to the DNA-binding transcription factor annotation guidelines, a more specific term should be used, such as "DNA-binding transcription activator activity, RNA polymerase II-specific" (GO:0001228) which would be more appropriate based on SMAD2's known function.

  3. The guideline also suggests that each transcriptional target should be captured separately, but no specific targets are indicated in this model.

  4. Missing SMAD Complex Formation:

  5. SMAD2 typically forms a complex with SMAD4 before translocating to the nucleus and activating transcription. This SMAD2-SMAD4 complex formation is not represented in the model.

  6. SMAD Phosphorylation:

  7. The activation of SMAD2 by TGFBR1 typically involves phosphorylation of SMAD2 at specific serine residues (Ser465/467), which is an important mechanistic detail that could be included in the model.

  8. Additional Regulatory Mechanisms:

  9. The model doesn't capture negative regulators of the pathway, such as inhibitory SMADs (SMAD7) or phosphatases like PPM1A that dephosphorylate SMAD2.

  10. It also doesn't include non-SMAD pathways activated by TGF-beta signaling.

  11. Specific Transcriptional Outputs:

  12. No specific transcriptional targets of SMAD2 are indicated. According to the DNA-binding transcription factor annotation guidelines, the relationship between the transcription factor and the genes it regulates should be captured with "has input" relationships.

Compliance with GO-CAM Best Practices

  1. The model follows the basic GO-CAM format with activities, cellular components, and causal relationships.

  2. The use of the "directly positively regulates" (RO:0002629) predicate is appropriate for the signaling cascade depicted.

  3. All proteins have appropriate molecular functions and cellular components assigned.

  4. However, as noted above, the DNA-binding transcription factor activity of SMAD2 could be more specifically annotated following the transcription factor annotation guidelines.

Recommendation

The model provides a good foundation for representing the TGF-beta signaling pathway, but could be enhanced by:

  1. Using more specific GO terms for SMAD2's transcription factor activity
  2. Including SMAD4 and the formation of the SMAD2-SMAD4 complex
  3. Adding specific transcriptional targets of SMAD2 with "has input" relationships
  4. Including additional regulatory mechanisms such as inhibitory SMADs
  5. Capturing the phosphorylation of SMAD2 by TGFBR1 more explicitly

These enhancements would make the model more comprehensive and aligned with the current understanding of TGF-beta signaling and GO-CAM best practices for annotating transcription factors.