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Based on my review of the GO-CAM model and the relevant research, I'll now provide a comprehensive analysis of the insulin receptor signaling pathway 2 (Mouse) model.

Review of GO-CAM Model: Insulin Receptor Signaling Pathway 2 (Mouse)

Model Overview

The model gomodel:62b4ffe300006559 titled "Insulin receptor signaling pathway 2 (Mouse)" represents the insulin signaling pathway in mouse cells (NCBITaxon:10090). According to the model comments, it was sourced from Reactome pathways R-HSA-74751 and R-HSA-74752.

Model Structure and Content

The model represents the insulin receptor signaling pathway, depicting:

  • Insulin binding to its receptor
  • Receptor activation
  • IRS-1/2 (Insulin Receptor Substrate) adaptor protein signaling
  • PI3K pathway activation
  • PDK1 and Akt activation
  • Downstream signaling effects

The model includes 9 primary activities represented by molecular function associations and their connections via causal associations:

  1. Insulin ligand activity (receptor ligand activity)
  2. Insulin receptor activity
  3. Protein tyrosine kinase activity of insulin receptor
  4. Protein-macromolecule adaptor activity of IRS proteins
  5. Molecular adaptor activity of IRS2
  6. Kinase activator activity of PIK3R1
  7. 1-phosphatidylinositol-3-kinase activity of PIK3CA
  8. 3-phosphoinositide-dependent protein kinase activity of PDPK1
  9. Kinase activity of AKT1

Entities and Gene Products in the Model

The model includes the following key gene products:

  • MGI:MGI:96572 (Ins1) and MGI:MGI:96573 (Ins2) - Mouse insulin
  • MGI:MGI:96575 (Insr) - Insulin receptor
  • MGI:MGI:99454 (Irs1) - Insulin receptor substrate 1
  • MGI:MGI:109334 (Irs2) - Insulin receptor substrate 2
  • MGI:MGI:97583 (Pik3r1) - Phosphatidylinositol 3-kinase regulatory subunit alpha
  • MGI:MGI:1206581 (Pik3ca) - Phosphatidylinositol 3-kinase catalytic subunit alpha
  • MGI:MGI:1338068 (Pdpk1) - 3-phosphoinositide-dependent protein kinase 1
  • MGI:MGI:87986 (Akt1) - RAC-alpha serine/threonine-protein kinase

Evidence and References

The model is supported by multiple types of evidence including: - Experimental evidence from direct assays (ECO:0000314) - Mutant phenotype evidence (ECO:0000315) - Genetic interaction evidence (ECO:0000316) - Sequence orthology evidence (ECO:0000266)

Key references include several publications (PMID:29512653, PMID:23886629, PMID:19047061, among others) that describe the insulin signaling pathway components and their interactions.

Consistency with GO-CAM Best Practices

1. Representation of Signaling Receptor Activity

The insulin signaling pathway model follows the guidelines from the "Signaling receptor activity annotation guidelines" document:

  • Ligand representation: The model correctly represents both Ins1 and Ins2 as enabling receptor ligand activity (GO:0048018)
  • Causal relation: The model correctly uses "directly positively regulates" (RO:0002629) as the causal relation between insulin ligand activity and insulin receptor activity
  • Receptor activity: The model correctly shows the insulin receptor enabling signaling receptor activity (GO:0005009)

2. Use of Molecular Adaptors

I verified that IRS1 and IRS2 are properly represented as molecular adaptors in the model, following the "How to annotate molecular adaptors" guidelines:

  • Both IRS1 and IRS2 have "protein-macromolecule adaptor activity" (GO:0030674)
  • The proper causal relations are used to connect these adaptors to downstream events
  • The model correctly shows IRS1/2 bringing together the insulin receptor and downstream signaling components

3. Pathway Coherence

The model demonstrates a coherent pathway from insulin binding to downstream effects: 1. Insulin binds to insulin receptor 2. Insulin receptor activates via tyrosine kinase activity 3. Activated receptor signals through adaptors IRS1/2 4. PI3K activation occurs (Pik3r1 and Pik3ca) 5. PDK1 (Pdpk1) is activated 6. Akt1 is activated

The flow of activities and causal connections is consistent with current understanding of the insulin signaling pathway.

Scientific Accuracy

The model accurately represents the core components of the insulin signaling pathway as described in the literature:

  1. Insulin-receptor binding: Aligns with the structure shown in PMID:29512653, which details the insulin receptor-insulin complex and activation mechanism.

  2. IRS protein function: Correctly shows IRS1/2 proteins as adaptors that enable downstream signaling after receptor activation, consistent with published data.

  3. PI3K-PDK1-Akt signaling: The model correctly represents this canonical pathway where PI3K activates PDK1, which then activates Akt. This is consistent with both PMID:19047061 and PMID:23886629.

  4. Biological process context: All activities are appropriately shown as part of the insulin receptor signaling pathway (GO:0008286).

Areas for Improvement

While the model is generally well-constructed, there are a few potential areas for improvement:

  1. Complete signaling cascade: The model could be extended to include:
  2. GSK3 phosphorylation and inhibition by Akt
  3. FOXO transcription factor regulation
  4. mTOR signaling pathway connections

  5. Glucose transporter (GLUT4) translocation

  6. Feedback mechanisms: The model could include negative feedback loops that regulate insulin signaling, such as:

  7. S6K-mediated negative feedback on IRS1

  8. Phosphatases that dephosphorylate key signaling components

  9. Crosstalk with other pathways: The model could include connections to:

  10. MAPK pathway

  11. Stress response pathways that modulate insulin signaling

  12. Additional regulatory components: The model could include:

  13. SOCS proteins that regulate insulin signaling
  14. Other adaptor proteins like SHC

  15. PTP1B phosphatase that dephosphorylates the insulin receptor

  16. Subcellular location: While not strictly required, cellular component annotations could be added to provide context about where these processes occur.

Conclusion

The GO-CAM model gomodel:62b4ffe300006559 provides a scientifically accurate representation of the core insulin receptor signaling pathway in mouse. The model follows GO-CAM best practices for representing signaling receptor activity and molecular adaptors.

The model has strong evidential support from both experimental data and published literature. All components are appropriately linked through causal relations that reflect their biological relationships.

While the model could be expanded to include more regulatory components and connections to other pathways, it successfully captures the central elements of insulin receptor signaling and serves as a valuable resource for understanding this critical pathway.