Skip to content

Based on all the information gathered, I'll now review the GO-CAM model with ID gomodel:66b5638000000102.

Review of GO-CAM Model: gomodel:66b5638000000102 - "PVR-CD226 mediated NK-cell cytotoxicity (Human)"

Overview of the Model

The model describes the PVR (CD155)-CD226 signaling pathway involved in natural killer (NK) cell cytotoxicity in humans. This signaling cascade is important for immune surveillance, particularly against tumor cells. The model captures:

  1. The interaction between PVR (CD155) on target cells and CD226 (DNAM-1) on NK cells
  2. The subsequent activation of GRB2 as a molecular adaptor
  3. GRB2's activation of VAV1, which functions as a guanyl-nucleotide exchange factor
  4. All these events occurring as part of natural killer cell-mediated cytotoxicity

Detailed Review

Biological Accuracy

The model accurately represents the established molecular interactions in this pathway:

  1. PVR (P15151) functioning as a receptor ligand on target cells:
  2. PVR/CD155 is correctly annotated with receptor ligand activity (GO:0048018)

  3. According to UniProt data, PVR indeed mediates NK cell adhesion and triggers NK cell effector functions by binding to CD226

  4. CD226 (Q15762) as the signaling receptor:

  5. CD226/DNAM-1 is correctly annotated with signaling receptor activity (GO:0038023)
  6. CD226 is known to be an activation receptor on NK cells that binds PVR/CD155

  7. The literature supports this interaction (PMID:15039383)

  8. GRB2 (P62993) as the adaptor protein:

  9. GRB2 is correctly annotated with protein-macromolecule adaptor activity (GO:0030674)
  10. GRB2 is known to function downstream of CD226 activation

  11. Its role in nucleating signaling complexes (PMID:25870599) aligns with its representation in the model

  12. VAV1 (P15498) as a GEF downstream of GRB2:

  13. VAV1 is correctly annotated with guanyl-nucleotide exchange factor activity (GO:0005085)

  14. VAV1 is known to be activated downstream of GRB2 in NK cell activation pathways

  15. Causal relationships:

  16. The causal relationships using RO:0002629 (directly positively regulates) properly connect the activity flow from PVR to CD226 to GRB2 to VAV1
  17. This accurately represents the directional signal flow in the pathway

Structural Review

The model follows GO-CAM best practices for signaling pathways:

  1. Enabled by associations: Each activity is correctly associated with the proteins that enable them

  2. Part of associations: All activities are appropriately designated as part of "natural killer cell mediated cytotoxicity" (GO:0042267)

  3. Occurs in associations: Proper cellular compartments are specified:

  4. PVR and CD226 at the plasma membrane (GO:0005886)

  5. GRB2 and VAV1 in the cytoplasm (GO:0005737)

  6. Causal associations: The direct positive regulation (RO:0002629) is correctly used to connect sequential activities in the pathway

  7. Evidence codes: Appropriate evidence codes are used with relevant PMIDs for each assertion

Suggested Improvements

While the model is generally well-constructed, I have the following suggestions for improvement:

  1. More detailed mechanistic representation:

  2. Consider representing the phosphorylation events involved. Based on the literature, CD226 engagement leads to tyrosine phosphorylation and recruitment of GRB2. This molecular detail could be added.

  3. Additional pathway components:

  4. The role of LFA-1, which cooperates with CD226 in triggering cytotoxicity (as mentioned in PMID:15039383), could be incorporated.

  5. The connection to downstream effector mechanisms of NK cell cytotoxicity (perforin/granzyme release) could be added to make the model more complete.

  6. Complex formation:

  7. According to the "How to annotate complexes in GO-CAM" document, if specific activities are carried out by a complex (rather than individual proteins), this should be represented.

  8. The literature suggests that CD226 forms complexes with other molecules upon activation, which could be captured.

  9. Downstream consequences:

  10. The model could be extended to include the ultimate outcomes of this pathway, such as target cell lysis or cytokine production.

Conclusion

The GO-CAM model "PVR-CD226 mediated NK-cell cytotoxicity (Human)" (gomodel:66b5638000000102) provides an accurate representation of the core signaling pathway from PVR-CD226 interaction to VAV1 activation in NK cell-mediated cytotoxicity. The model adheres to GO-CAM best practices and is well-supported by scientific literature.

The model could be enhanced by adding more molecular details of the activation events, representing relevant protein complexes, and extending the pathway to include additional cooperating receptors and downstream effects. Nevertheless, in its current form, it provides a valuable representation of this important immune surveillance pathway.