Based on my review of the GO-CAM model and the corresponding literature, I'll now provide a comprehensive review of the model "IL6:sIL6R Trans-signaling pathway (Human)" (gomodel:5f46c3b700002685).

GO-CAM Review: IL6:sIL6R Trans-signaling pathway (Human)¶

Model Summary¶

This GO-CAM model (ID: gomodel:5f46c3b700002685) represents the IL-6 trans-signaling pathway in humans. It includes the components of the IL-6:sIL6R trans-signaling complex and the subsequent JAK-STAT pathway activation. The model encompasses the following key steps: 1. IL-6 cytokine activity 2. IL-6 binding to the soluble IL-6 receptor (sIL6R) 3. IL-6:sIL6R complex binding to gp130 (IL6ST) 4. Activation of JAK1 kinase 5. Phosphorylation and activation of STAT3 6. Negative regulation by SOCS3

Overall Structure Assessment¶

The model correctly captures the major components and causal relationships in the IL-6 trans-signaling pathway. The annotated biological process, molecular functions, and cellular locations are generally appropriate according to the literature and GO-CAM best practices.

The representation is consistent with the hexameric structure of the IL-6/IL-6R/gp130 complex as described by Boulanger et al. (PMID:12829785), and properly represents the JAK-STAT signaling cascade that follows receptor activation.

Detailed Review of Model Components¶

Activity 1: IL-6 Cytokine Activity¶

Protein: UniProtKB:P05231 (IL6 Hsap)
Molecular Function: GO:0005125 (cytokine activity)
Occurs in: GO:0005615 (extracellular space)
Part of: GO:0070102 (interleukin-6-mediated signaling pathway)

Assessment: This component is correctly annotated. IL-6 is a secreted cytokine that acts in the extracellular space to initiate signaling. The cytokine activity molecular function is appropriate.

Activity 2: IL-6 Receptor Activity (soluble form)¶

Protein: UniProtKB:P08887-2 (IL6R Hsap)
Molecular Function: GO:0004896 (cytokine receptor activity)
Occurs in: GO:0005615 (extracellular space)
Part of: GO:0070102 (interleukin-6-mediated signaling pathway)

Assessment: This annotation is correct for the soluble form of IL-6R (sIL6R). The soluble form is appropriately identified by the protein isoform UniProtKB:P08887-2, which is the alternatively spliced shorter form lacking the transmembrane and cytoplasmic domains. The location in the extracellular space is also correct.

Activity 3: GP130 Receptor Activation¶

Protein: UniProtKB:P40189 (IL6ST Hsap)
Molecular Function: GO:0030296 (protein tyrosine kinase activator activity)
Occurs in: GO:0005886 (plasma membrane)
Part of: GO:0070102 (interleukin-6-mediated signaling pathway)

Assessment: This annotation is correct. GP130 (IL6ST) acts as an activator of tyrosine kinases, particularly JAK1. The localization to the plasma membrane is appropriate, as gp130 is a transmembrane protein.

Activity 4: JAK1 Kinase Activity¶

Protein: UniProtKB:P23458 (JAK1 Hsap)
Molecular Function: GO:0004713 (protein tyrosine kinase activity)
Occurs in: GO:0009898 (cytoplasmic side of plasma membrane)
Part of: GO:0007259 (cell surface receptor signaling pathway via JAK-STAT)

Assessment: This annotation is correct. JAK1 is a tyrosine kinase that associates with the cytoplasmic domain of gp130 and is activated upon receptor dimerization. The cellular location on the cytoplasmic side of the plasma membrane is accurate.

Activity 5: STAT3 Transcription Factor Activity¶

Protein: UniProtKB:P40763 (STAT3 Hsap)
Molecular Function: GO:0003700 (DNA-binding transcription factor activity)
Occurs in: GO:0005634 (nucleus)
Part of: GO:0007259 (cell surface receptor signaling pathway via JAK-STAT)

Assessment: This annotation is correct. Once phosphorylated by JAK1, STAT3 dimerizes and translocates to the nucleus where it acts as a transcription factor. The localization to the nucleus for this activity is appropriate.

Activity 6: SOCS3 Inhibitory Activity¶

Protein: UniProtKB:O14543 (SOCS3 Hsap)
Molecular Function: GO:0004860 (protein kinase inhibitor activity)
Occurs in: GO:0009898 (cytoplasmic side of plasma membrane)
Part of: GO:0007259 (cell surface receptor signaling pathway via JAK-STAT)

Assessment: This annotation is correct. SOCS3 is a negative regulator of the JAK-STAT pathway that inhibits JAK1 kinase activity. Its location at the cytoplasmic side of the plasma membrane is appropriate since it interacts with the activated receptor complex.

Causal Relationships Assessment¶

The model includes the following causal relationships:

IL-6 cytokine activity (Activity 1) → directly positively regulates → IL-6 receptor activity (Activity 2)
IL-6 receptor activity (Activity 2) → directly positively regulates → GP130 activation (Activity 3)
GP130 activation (Activity 3) → directly positively regulates → JAK1 kinase activity (Activity 4)
JAK1 kinase activity (Activity 4) → directly positively regulates → STAT3 transcription factor activity (Activity 5)
STAT3 transcription factor activity (Activity 5) → provides input for → SOCS3 inhibitor activity (Activity 6)
SOCS3 inhibitor activity (Activity 6) → directly negatively regulates → JAK1 kinase activity (Activity 4)

Assessment: The causal relationships in the model correctly capture the flow of signaling from IL-6 binding to its receptor, through the activation of JAK1 and STAT3, and the negative feedback loop provided by SOCS3. The use of the "directly positively regulates" (RO:0002629) relation for the activating steps and "directly negatively regulates" (RO:0002630) for the inhibitory step by SOCS3 is appropriate according to GO-CAM best practices.

Literature Support¶

The annotations are supported by appropriate literature references:

PMID:12829785 (Boulanger et al., 2003): Describes the hexameric structure of the IL-6/IL-6R/gp130 complex
PMID:21990364 (Garbers et al., 2011): Covers the role of sIL6R in trans-signaling
PMID:8272873 (Stahl et al., 1994): Details the JAK-STAT pathway activation by IL-6
PMID:9727029: Evidence for SOCS3 inhibition of JAK1
PMID:19915009: Evidence for gp130 localization to the plasma membrane
PMID:17344214: Evidence for STAT3 transcription factor activity

The evidence is well-documented with appropriate ECO codes (e.g., ECO:0000314 for direct assay evidence).

Compliance with GO-CAM Best Practices¶

The model follows GO-CAM best practices for:

Signaling receptor annotation: The model correctly represents the distinction between the ligand (IL-6), the receptor (IL-6R), and the co-receptor/signal transducer (gp130/IL6ST) according to the "Signaling receptor activity annotation guidelines".
Regulation representation: The regulatory relationships between activities follow the "Regulation and Regulatory Processes in GO-CAM" guidelines, properly capturing direct positive and negative regulation.
Complex representation: The model appropriately represents the activities of the proteins in the IL-6/IL-6R/gp130 complex without explicitly representing the complex as a whole entity, which is consistent with "How to annotate complexes in GO-CAM" guidelines when the activities of individual subunits are known.

Suggestions for Improvement¶

While the model is generally well-constructed, there are a few potential improvements:

Completeness of STAT3 signaling: The model could be extended to include some of the downstream targets of STAT3 transcriptional activity to provide a more complete picture of the pathway outcome.
Alternative membrane-bound pathway: Consider adding or referencing a companion model for the classic IL-6 signaling pathway (via membrane-bound IL-6R) to highlight the differences between classical and trans-signaling.
IL6ST isoform specification: The model uses UniProtKB:P40189 for IL6ST, but could specifically reference the isoform involved in signaling (e.g., UniProtKB:P40189-1) for greater precision, similar to how it specifies the IL6R isoform.

Conclusion¶

The GO-CAM model "IL6:sIL6R Trans-signaling pathway (Human)" accurately represents the molecular activities and causal relationships in the IL-6 trans-signaling pathway. It is well-supported by literature references and follows GO-CAM best practices. The model provides a valuable resource for understanding the mechanisms of IL-6 trans-signaling and its role in inflammatory processes.

The representation of the IL-6/sIL-6R/gp130 complex and the subsequent JAK-STAT signaling is consistent with current knowledge of this pathway. With the minor suggested improvements, this model could serve as an exemplary representation of cytokine receptor signaling in the GO-CAM framework.