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Based on the information I have gathered, I will now provide a comprehensive review of the GO-CAM model with ID 62900b6400001630, titled "PTEN in excitatory hippocampal synapse long-term depression (Human)".

Review of GO-CAM Model: PTEN in excitatory hippocampal synapse long-term depression (Human)

Model Overview

  • Model ID: gomodel:62900b6400001630
  • Title: PTEN in excitatory hippocampal synapse long-term depression (Human)
  • Taxon: Human (NCBITaxon:9606)
  • Status: Production
  • Last automated change: 2023-03-16: RO:0002213 replaced by RO:0002629

Model Structure and Components

This model depicts a signaling pathway involved in hippocampal long-term depression (LTD) in humans, focusing on the role of PTEN (phosphatase and tensin homolog). The model includes 5 key molecular activities connected through causal relationships:

  1. NMDA glutamate receptor activity (GO:0004972)
  2. Enabled by: NMDA receptor complex (GO:0017146)
  3. Occurs in: Postsynaptic density, intracellular component (GO:0099092)
  4. Part of: Long-term synaptic depression (GO:0060292)

  5. Has input: L-glutamate (CHEBI:29985)

  6. Synaptic receptor adaptor activity (GO:0030160)

  7. Enabled by: DLG4 (UniProtKB:P78352)
  8. Occurs in: Postsynaptic density, intracellular component (GO:0099092)

  9. Part of: Long-term synaptic depression (GO:0060292)

  10. Phosphatidylinositol phosphate phosphatase activity (GO:0052866)

  11. Enabled by: PTEN (UniProtKB:P60484)
  12. Occurs in: Postsynaptic density, intracellular component (GO:0099092)

  13. Part of: Long-term synaptic depression (GO:0060292)

  14. Transcription coactivator activity (GO:0003713)

  15. Enabled by: CTNNB1/β-catenin (UniProtKB:P35222)
  16. Occurs in: Chromatin (GO:0000785)

  17. Part of: Positive regulation of transcription by RNA polymerase II (GO:0045944)

  18. Glycine transmembrane transporter activity (GO:0015187)

  19. Enabled by: SLC6A20 (UniProtKB:Q9NP91)
  20. Occurs in: Postsynaptic membrane (GO:0045211)
  21. Part of: Glycine import across plasma membrane (GO:1903804)
  22. Has input/output: Glycine zwitterion (CHEBI:57305)

Causal Relationships in the Model

The model depicts the following causal relationships: 1. NMDA receptor complex activity (GO:0004972) directly positively regulates (RO:0002629) synaptic receptor adaptor activity (GO:0030160) of DLG4 2. DLG4's adaptor activity directly positively regulates (RO:0002629) PTEN's phosphatase activity (GO:0052866) 3. PTEN's phosphatase activity causally upstream with negative effect (RO:0002305) on β-catenin's transcription coactivator activity (GO:0003713) 4. β-catenin's transcription activity provides input for (RO:0002407) SLC6A20's glycine transporter activity (GO:0015187)

Evidence Assessment

The model uses various evidence codes and references: - Most activities are supported by sequence similarity evidence (ECO:0000250) or curator inference (ECO:0000305) - β-catenin's transcription activity is supported by direct assay evidence (ECO:0000314) - Evidence is primarily based on mouse studies and extrapolated to human proteins - Key references include PMID:20628354, PMID:31866820, and PMID:33428810

Quality Assessment

Strengths:

  1. Biological accuracy: The model correctly represents the role of PTEN in regulating β-catenin activity and subsequently SLC6A20 expression, consistent with the literature.
  2. Appropriate evidence: The model uses appropriate evidence codes for the transferred annotations from mouse studies.
  3. Proper use of ontology terms: The activities, cellular locations, and causal relationships use appropriate GO and RO terms.

Issues/Concerns:

  1. Input/Output confusion: SLC6A20 has both "has_input" and "has_output" relationships with glycine zwitterion (CHEBI:57305). This is contradictory as a transporter typically moves molecules in one direction. The literature suggests SLC6A20 primarily imports glycine, so having both input and output is confusing.

  2. Missing key components: Based on the literature (PMID:33428810), there is a regulatory relationship where PTEN deletion increases β-catenin binding to the SLC6A20 promoter. The model shows PTEN negatively regulating β-catenin, but the intermediate steps (likely involving PI3K/AKT pathway) are missing.

  3. Potential mismatch with human biology: The model is annotated for human proteins, but much of the evidence comes from mouse studies. The papers indicate some differences between mouse and human SLC6A20 genes (mice have two genes, SLC6A20A and SLC6A20B, while humans have one).

  4. Functional discrepancy in RO:0002407 usage: The model uses "provides input for" (RO:0002407) between β-catenin's transcription activity and SLC6A20 transporter activity. This seems to conflate transcriptional regulation with direct molecular input. It would be more accurate to use a term that indicates transcriptional regulation.

  5. Missing causal connection: The relationship between SLC6A20's glycine transport and NMDA receptor function (which requires glycine as a co-agonist) is not explicitly modeled, despite being central to the biological story in the referenced papers.

Recommendations for Improvement

  1. Correct the SLC6A20 input/output inconsistency: Remove the "has_output" relationship for glycine, as SLC6A20 primarily imports glycine into cells, reducing extracellular glycine concentration.

  2. Add intermediate signaling components: Consider adding the PI3K/AKT pathway components that mediate PTEN's regulation of β-catenin nuclear translocation.

  3. Complete the signaling loop: Add a causal relationship showing how SLC6A20-mediated reduction in extracellular glycine affects NMDA receptor function to complete the biological story.

  4. Use more appropriate relationship term: Replace RO:0002407 (provides input for) with a relationship term that better captures transcriptional regulation.

  5. Add clarifying comments: Add notes to explain the transfer of evidence from mouse to human and any potential species-specific differences in the pathway.

Conclusion

The GO-CAM model correctly captures the core components of PTEN's role in regulating hippocampal synaptic depression through β-catenin and SLC6A20, but has several issues that should be addressed to improve its accuracy and clarity. The most critical issues are the contradictory input/output relationships for SLC6A20 and the missing causal connection between SLC6A20 and NMDA receptor function. Addressing these issues would make the model a more accurate representation of the biological pathway described in the literature.