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5ce58dde00001215 Mouse Aatf antiapoptosis

Now let me also check the information in the referenced PMID in the GO-CAM model to understand the functional relationship between these proteins:

Let me analyze the GO-CAM model and review it based on the information I've collected and the GO-CAM guidelines.

Review of GO-CAM Model 5ce58dde00001215 "Mouse-Aatf-antiapoptosis"

Overview of the Model:

This GO-CAM model describes the role of AATF (Apoptosis Antagonizing Transcription Factor) in protecting cells from ER stress-mediated apoptosis in mouse pancreatic beta cells, primarily through regulating the transcription factor activity of a complex containing AATF and STAT3, which then activates AKT1 expression.

Model Components:

  1. Core Proteins:
  2. AATF (MGI:MGI:1328355): Anti-apoptotic factor that protects cells from ER stress-mediated cell death
  3. STAT3 (MGI:MGI:103038): Transcription factor that forms a complex with AATF

  4. AKT1 (MGI:MGI:87986): Serine/threonine kinase with anti-apoptotic functions

  5. Biological Context:

  6. This pathway operates in type B pancreatic cells (CL:0000169)
  7. It's part of the endoplasmic reticulum unfolded protein response (GO:0030968)

  8. Leads to negative regulation of intrinsic apoptotic signaling pathway (GO:2001243)

  9. Functional Relationships:

  10. XBP1 positively regulates AATF
  11. ERN1 positively regulates AATF
  12. AATF and ERN1 positively regulate STAT3-containing transcription complex
  13. EIF2AK3 positively regulates EIF2A which regulates STAT3-containing complex
  14. AATF-STAT3 complex directly positively regulates AKT1
  15. AKT1 inhibits apoptosis

Assessment of Model according to GO-CAM Guidelines:

Strengths:

  1. Accurate molecular functions: The transcription factor complex containing AATF and STAT3 is properly annotated with DNA-binding transcription factor activity (GO:0003700), which is appropriate based on the role of this complex in transcriptional regulation.

  2. Clear causal relationships: The model uses appropriate causal associations:

  3. RO:0002304 "causally upstream of, positive effect" for upstream regulators
  4. RO:0002629 "directly positively regulates" for the STAT3 complex's effect on AKT1

  5. RO:0004047 (which appears in the model) for EIF2A's relationship with the complex

  6. Cellular context: The model includes the cellular location (nucleus GO:0005634 for the transcription complex; pancreatic beta cells CL:0000169 for AATF).

  7. Biological process context: Components are correctly annotated as part of the ER unfolded protein response (GO:0030968).

Areas for Improvement:

  1. Complex Representation: According to the "How to annotate complexes in GO-CAM" document, when using a protein complex (GO:0005667 transcription regulator complex), the model should indicate which specific proteins carry the molecular activities. Here, the model correctly shows that both STAT3 and AATF are in the complex, but:

  2. The composition of the complex is incomplete, as based on the literature, this complex formation is enhanced by STAT3 binding to phosphorylated AATF, and this relationship isn't captured.

  3. According to the reference PMID:19911006, AATF and STAT3 interact directly, and this interaction enhances the binding of STAT3 to the AKT1 promoter, but this mechanistic detail isn't fully captured.

  4. Missing Phosphorylation Events: The PMID:19911006 reference emphasizes the importance of phosphorylation:

  5. AATF is induced by ER stress through PERK-eIF2alpha phosphorylation
  6. STAT3 phosphorylation is enhanced by AATF
  7. AKT phosphorylation is also important for its activity

These phosphorylation events are critical for the pathway functionality but aren't captured in the model.

  1. Incomplete Biological Processes: The terminal effect of this pathway is properly captured as "negative regulation of intrinsic apoptotic signaling pathway," but intermediate processes like "transcriptional regulation of AKT1" could have been included.

  2. Evidence Codes: While the model uses appropriate evidence codes (ECO:0000315 for mutant phenotype evidence and ECO:0000314 for direct assay evidence), some of the relationships might benefit from more specific evidence annotations.

  3. Missing Inputs for Transcription Factor Activity: According to the "DNA-binding transcription factor activity annotation guidelines," the transcription factor activity should have "has input" relationships to the gene it regulates. The model shows that the complex directly positively regulates AKT1 activity, but doesn't explicitly show that it regulates AKT1 gene expression.

Recommendations for Improvement:

  1. Add Phosphorylation States: Include the critical phosphorylation events (especially for STAT3 at Tyr-705 and Ser-727, and AATF phosphorylation by PERK pathway).

  2. Refine Complex Representation: Better specify the molecular interaction between AATF and STAT3 and how this interaction enhances STAT3 DNA binding.

  3. Complete the Transcriptional Regulation Representation: Add "has input" relationship from the transcription complex to the AKT1 gene, as per the transcription factor annotation guidelines.

  4. Add More Specific Biological Process Terms: Include intermediate processes like "regulation of AKT1 transcription" to better represent the mechanistic details.

  5. Enhance Cellular Context: Add more detailed subcellular localization for different components of the pathway, especially the translocation events mentioned in the paper.

Conclusion:

This GO-CAM model provides a good representation of AATF's role in protecting cells from ER stress-induced apoptosis through promoting AKT1 expression via the STAT3 transcription factor complex. The model correctly captures the major players and relationships, but could be enhanced by including more mechanistic details about phosphorylation events, complex formation, and transcriptional regulation specifics.

The model is consistent with the reference literature (PMID:19911006) and follows GO-CAM best practices, though some refinements would make it even more informative and mechanistically accurate.