Skip to content

Based on my examination of the GO-CAM model and relevant documentation, I'll now provide a comprehensive review of the GO-CAM model gomodel:65d7e4ac00002427.

Review of GO-CAM Model: MICA-NKG2D mediated NK cell cytotoxicity (Human)

Overview

This model (gomodel:65d7e4ac00002427) represents the molecular mechanism of natural killer (NK) cell cytotoxicity mediated by the interaction between MICA (MHC class I polypeptide-related sequence A) and NKG2D (KLRK1, killer cell lectin-like receptor subfamily K member 1). The model shows how MICA, a stress-induced ligand, activates the NKG2D receptor on NK cells, leading to downstream signaling events that result in NK cell-mediated cytotoxicity.

Model Structure and Components

The model includes the following key components:

  1. Ligand (MICA) - Receptor (NKG2D) interaction:
  2. MICA (UniProtKB:Q29983) enables receptor ligand activity (GO:0048018)
  3. NKG2D/KLRK1 (UniProtKB:P26718) enables signaling receptor activity (GO:0038023)

  4. MICA directly positively regulates NKG2D

  5. Signaling adaptor (HCST/DAP10):

  6. HCST (UniProtKB:Q9UBK5) enables protein-macromolecule adaptor activity (GO:0030674)

  7. NKG2D directly positively regulates HCST

  8. Downstream signaling components:

  9. HCST directly positively regulates multiple downstream components:

    • VAV1 (UniProtKB:P15498) with guanyl-nucleotide exchange factor activity (GO:0005085)
    • GRB2 (UniProtKB:P62993) with guanyl-nucleotide exchange factor adaptor activity (GO:0005091)
    • PIK3R1 (UniProtKB:P27986) with phosphatidylinositol 3-kinase regulator activity (GO:0035014)

  10. Cellular context:

  11. All activities are part of natural killer cell mediated cytotoxicity (GO:0042267)
  12. MICA and NKG2D occur in plasma membrane (GO:0005886)
  13. HCST downstream components (VAV1, GRB2, PIK3R1) occur in cytoplasm (GO:0005737)

Strengths of the Model

  1. Accurate molecular representation: The model correctly captures the MICA-NKG2D interaction and subsequent signaling through HCST/DAP10, which is supported by literature (as seen in UniProt entries).

  2. Proper adaptor annotation: HCST/DAP10 is correctly annotated as having protein-macromolecule adaptor activity, consistent with the "How to annotate molecular adaptors" guidelines.

  3. Complete signaling pathway: The model represents a complete signaling pathway from extracellular ligand to intracellular effectors, providing a comprehensive view of NK cell activation.

  4. Proper evidence usage: Each activity and relation is supported by appropriate evidence codes and literature references.

  5. Appropriate cellular location annotations: The model correctly locates activities in their respective cellular compartments.

Suggested Improvements

  1. Activity flow representation: While the overall structure is correct, the signaling flow could be clarified by ensuring that the downstream components (VAV1, GRB2, PIK3R1) are connected to further downstream effectors if information is available. Currently, these proteins represent the endpoint of the signaling pathway in the model.

  2. Complex representation: According to the UniProt entries, NKG2D and HCST form a heterohexameric complex (4 HCST + 2 NKG2D). The model could potentially include a representation of this complex structure according to the "How to annotate complexes in GO-CAM" guidelines, although the current representation with direct relationships is also valid.

  3. PIK3R1 functional outcome: The model shows PIK3R1 with phosphatidylinositol 3-kinase regulator activity but doesn't show the downstream effects on PI3K signaling. If literature supports it, adding these connections would enhance the completeness of the pathway.

Consistency with GO-CAM Guidelines

The model follows GO-CAM best practices for:

  1. Signaling receptor annotation: The model correctly follows the "Signaling receptor activity annotation guidelines" by showing MICA as having receptor ligand activity directly positively regulating NKG2D's signaling receptor activity.

  2. Molecular adaptor annotation: HCST/DAP10 is properly annotated as having protein-macromolecule adaptor activity, with appropriate causal relations to downstream components, consistent with "How to annotate molecular adaptors" guidelines.

  3. Evidence and references: Each association has appropriate evidence codes and literature references.

  4. Causal relations: The model uses the appropriate causal relations ("directly positively regulates") for the signaling cascade.

Biological Accuracy

The model accurately represents the known biology of MICA-NKG2D interaction based on the UniProt entries:

  1. MICA as stress-inducible ligand: MICA is correctly shown as a receptor ligand that activates NKG2D. According to UniProt, MICA is "upregulated in stressed conditions, such as viral and bacterial infections or DNA damage response".

  2. NKG2D signaling through HCST: The model correctly shows that NKG2D signals through HCST/DAP10, which is consistent with the UniProt entry stating that NKG2D "is not capable of signal transduction by itself, but operates through the adapter protein HCST".

  3. Downstream signaling events: The involvement of VAV1, GRB2, and PIK3R1 is consistent with literature, with UniProt noting that HCST "functions as a docking site for PI3-kinase PIK3R1 and GRB2".

Conclusion

The GO-CAM model gomodel:65d7e4ac00002427 is a biologically accurate representation of MICA-NKG2D mediated NK cell cytotoxicity that follows GO-CAM best practices. The model effectively captures the signaling cascade from ligand-receptor interaction to downstream signaling components. The model would benefit from additional downstream connections if information is available, but as presented, it provides a clear and accurate representation of this important immunological pathway.

This model serves as a good example of how GO-CAM can be used to represent receptor-ligand interactions and signal transduction pathways in the immune system.