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Now that I have gathered all the necessary information, I will conduct a comprehensive review of the GO-CAM model gomodel:66b5638000001291.

Review of GO-CAM Model: gomodel:66b5638000001291

Model Overview

Title: NECTIN2-CD226 mediated NK-cell cytotoxicity (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production
Model ID: gomodel:66b5638000001291

This model describes the molecular interactions involved in natural killer (NK) cell-mediated cytotoxicity through the NECTIN2 (CD112) and CD226 (DNAM-1) receptor-ligand pathway, leading to GRB2 adaptor protein recruitment and subsequent VAV1 activation.

Components of the Model

The model consists of four main molecular activities:

  1. NECTIN2 (Q92692): Receptor ligand activity (GO:0048018)
  2. CD226 (Q15762): Signaling receptor activity (GO:0038023)
  3. GRB2 (P62993): Protein-macromolecule adaptor activity (GO:0030674)
  4. VAV1 (P15498): Guanyl-nucleotide exchange factor activity (GO:0005085)

All these components participate in the biological process of natural killer cell-mediated cytotoxicity (GO:0042267).

Causal Relationships

The model shows three causal relationships with "directly positively regulates" (RO:0002629) predicate: 1. NECTIN2 (receptor ligand) → CD226 (signaling receptor) 2. CD226 (signaling receptor) → GRB2 (adaptor protein) 3. GRB2 (adaptor protein) → VAV1 (guanyl-nucleotide exchange factor)

This creates a linear signaling cascade where NECTIN2 binding to CD226 triggers downstream adaptor protein recruitment and eventual activation of VAV1.

Cellular Locations

  • NECTIN2 activity occurs at the plasma membrane (GO:0005886)
  • CD226 activity occurs at the plasma membrane (GO:0005886)
  • GRB2 activity occurs in the cytoplasm (GO:0005737)
  • VAV1 activity occurs in the cytoplasm (GO:0005737)

Evidence Assessment

Each activity and causal relationship is supported by experimental evidence:

  • The NECTIN2-CD226 interaction is supported by direct assay evidence (ECO:0000314) from PMID:15607800
  • CD226's signaling activity is supported by direct assay evidence (ECO:0000314) from PMID:15039383
  • GRB2's adaptor function is supported by direct assay evidence (ECO:0000314) from PMID:25870599
  • VAV1's GEF activity is supported by direct assay evidence (ECO:0000314) from PMID:8990121

Biological Significance

This model captures an important biological pathway in NK cell activation. When NECTIN2 (CD112) on a target cell binds to CD226 (DNAM-1) on an NK cell, it triggers a signaling cascade that contributes to natural killer cell-mediated cytotoxicity. This interaction is particularly important in immune surveillance against tumor cells that express NECTIN2.

Model Quality Assessment

Strengths:

  1. The model accurately represents the signaling pathway from NECTIN2-CD226 binding to VAV1 activation.
  2. Each component and relationship is supported by published experimental evidence.
  3. Cellular locations are correctly annotated for all molecules.
  4. The biological process (NK cell cytotoxicity) is correctly associated with all activities.

Areas for Improvement:

  1. Missing Protein Relationships: The literature indicates that CD226 can also interact with PVR (CD155) as another ligand. While the model focuses specifically on the NECTIN2-CD226 pathway, a note about this alternative pathway could be useful for completeness.

  2. Downstream Signaling: The model stops at VAV1 activation, but the literature indicates further downstream effects through the RAS/MAPK pathway. Extending the model to include these downstream effects would provide a more complete picture of the signaling cascade.

  3. Alternative Downstream Pathways: The literature suggests that CD226 signaling can also lead to PI3K/AKT pathway activation, which is not represented in this model.

  4. Molecular Details: The model doesn't capture the details of how CD226 activates GRB2. According to the literature, CD226 must be phosphorylated by Src family kinases to recruit GRB2, which then leads to activation of VAV1.

  5. Timing and Context: The model doesn't capture the context in which this pathway is activated, such as the presence of other co-stimulatory or inhibitory signals that might modulate NK cell activation.

Recommendations for Model Improvement

  1. Consider adding details about the phosphorylation of CD226 by Src family kinases before GRB2 recruitment.

  2. Include a note or representation of the alternative ligand PVR (CD155) that can also bind to CD226.

  3. Extend the model to include downstream effects of VAV1 activation, particularly the activation of small GTPases like RAC1 that lead to cytoskeletal reorganization and NK cell activation.

  4. Consider adding parallel pathways that might be activated by CD226 signaling, such as the PI3K/AKT pathway.

  5. Add information about how this pathway intersects with other pathways in NK cell activation to provide a more comprehensive view of NK cell cytotoxicity.

Conclusion

The GO-CAM model gomodel:66b5638000001291 accurately represents the core pathway of NECTIN2-CD226 mediated NK cell cytotoxicity from ligand binding to VAV1 activation. Each component and relationship is well-supported by experimental evidence. While there are opportunities to expand the model to include additional details and downstream events, the current model provides a solid foundation for understanding this important immune pathway.