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5fadbcf000001962 T helper 17 cell lineage commitment by IL6 cluster Human

Now, let me review the GO-CAM model based on the guidelines and best practices.

GO-CAM Model Review: "T-helper 17 cell lineage commitment by IL6 cluster (Human)" (gomodel:5fadbcf000001962)

Overview

This model represents the IL-6 signaling pathway leading to T-helper 17 cell lineage commitment in humans. It shows how IL-6 signaling through its receptor complex activates the JAK-STAT pathway, culminating in STAT3 activation and subsequent gene regulation, with feedback inhibition by SOCS3.

Biological Accuracy Assessment

  1. Pathway Flow:
  2. The model correctly represents the IL-6 signaling cascade:
    • IL-6 (P05231) → IL-6R (P08887-2) → gp130/IL6ST (P40189-2) → JAK1 (P23458) → STAT3 (P40763)
    • STAT3 regulates SOCS3 (O14543), which provides negative feedback to JAK1

  3. This is consistent with established knowledge of IL-6 signaling and the JAK-STAT pathway.

  4. Molecular Functions:

  5. IL-6: cytokine activity (GO:0005125) - correctly assigned
  6. IL-6R: cytokine receptor activity (GO:0004896) - correctly assigned
  7. IL-6ST/gp130: protein tyrosine kinase activator activity (GO:0030296) - correctly assigned for its role in activating JAK1
  8. JAK1: protein tyrosine kinase activity (GO:0004713) - correctly assigned
  9. STAT3: DNA-binding transcription factor activity (GO:0003700) - correctly assigned

  10. SOCS3: kinase inhibitor activity (GO:0019210) - correctly assigned for feedback inhibition

  11. Cellular Localization:

  12. IL-6: extracellular space (GO:0005615) - correct
  13. IL-6R: plasma membrane (GO:0005886) - correct
  14. IL-6ST: plasma membrane (GO:0005886) - correct
  15. JAK1: cytoplasmic side of plasma membrane (GO:0009898) - correct
  16. STAT3: nucleus (GO:0005634) - correct for activated STAT3
  17. SOCS3: cytosol (GO:0005829) - correct

Compliance with GO-CAM Best Practices

  1. Signaling Pathway Representation:

  2. The model follows the signaling receptor annotation guidelines:

    • Ligand (IL-6) has cytokine activity and occurs in extracellular space
    • Receptor components are properly located at the plasma membrane
    • Causal relationships use appropriate relations (RO:0002629 "directly positively regulates")

  3. Transcription Factor Annotation:

  4. STAT3 is correctly annotated as a DNA-binding transcription factor in the nucleus

  5. The causal relationship between JAK1 and STAT3 is appropriate

  6. Biological Process Context:

  7. Activities are properly placed in biological processes:

    • IL-6 signaling components in "interleukin-6-mediated signaling pathway" (GO:0070102)
    • JAK1, STAT3, and SOCS3 in "cell surface receptor signaling pathway via JAK-STAT" (GO:0007259)

  8. Causal Relationships:

  9. The model uses appropriate causal relations between activities:
    • "Directly positively regulates" (RO:0002629) for activation steps
    • "Directly negatively regulates" (RO:0002630) for SOCS3 inhibition of JAK1
    • "Contributes to" (RO:0002407) for STAT3's regulation of SOCS3

Evidence Support

The model cites multiple PMIDs with appropriate evidence codes: - PMID:12829785 - For IL-6 receptor signaling - PMID:8272873 - For JAK-STAT pathway components - PMID:19915009 - For IL6R-gp130 interactions - PMID:12754505 - For SOCS3 feedback inhibition

Issues Identified

  1. Minor Ontology Term Issue:

  2. The model contains a comment noting an automated term replacement: "GO:0005887 replaced by GO:0005886" (integral component of plasma membrane replaced by plasma membrane), which is appropriate.

  3. Evidence for STAT3-SOCS3 Relationship:

  4. The causal association between STAT3 and SOCS3 uses ECO:0000250 (sequence similarity evidence) with PMID:10359822. It would be preferable to have direct experimental evidence (ECO:0000314) for this specific human interaction.

  5. SOCS3 Pathway Placement:

  6. SOCS3's inhibition of JAK1 is supported by evidence from mouse (O35718), while it would be better to have human-specific evidence where possible.

  7. Missing Model Components:

  8. The model doesn't explicitly show the endpoint - T-helper 17 cell lineage commitment (GO:0072540) is in the model title but not clearly represented as the outcome of the pathway.

Recommendations for Improvement

  1. Include T-helper 17 cell lineage commitment:

  2. Add the biological process GO:0072540 (T-helper 17 cell lineage commitment) as a downstream process influenced by STAT3 transcription factor activity.

  3. Strengthen Evidence:

  4. Replace sequence similarity evidence (ECO:0000250) with direct experimental evidence (ECO:0000314) for human STAT3-SOCS3 relationship if available.

  5. Complete the Pathway:

  6. Consider adding STAT3 target genes specific to Th17 differentiation (e.g., RORC, IL17A) if this level of detail is desired.

  7. Update Evidence:

  8. Include more recent literature supporting the role of this pathway in Th17 differentiation if available.

Summary

The GO-CAM model "T-helper 17 cell lineage commitment by IL6 cluster (Human)" (gomodel:5fadbcf000001962) is a well-constructed model that accurately represents the IL-6 signaling pathway leading to STAT3 activation. It follows GO-CAM best practices for signaling pathways and transcription factor annotation. The model has strong evidence support from the literature.

The main improvements would be to explicitly represent the connection to T-helper 17 cell lineage commitment and possibly strengthen some of the evidence with human-specific data. Overall, this is a high-quality model that provides valuable information about IL-6 signaling in the context of T-helper 17 cell development.