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Based on my review of the GO-CAM model (gomodel:66b5638000001968) titled "PVR-TIGIT pair inhibits NK cell mediated cytotoxicity (Human)", I'll provide a comprehensive assessment of this model and its biological representation.

GO-CAM Review: "PVR-TIGIT pair inhibits NK cell mediated cytotoxicity (Human)"

Model Overview

This model represents the inhibitory signaling pathway in which the interaction between Poliovirus Receptor (PVR/CD155) and T-cell immunoglobulin and ITIM domain (TIGIT) suppresses natural killer (NK) cell-mediated cytotoxicity. The pathway involves multiple molecular functions including receptor ligand activity, signaling receptor activity, molecular adaptor activity, phosphatase activity, and kinase activity connected through a causal chain.

Biological Accuracy

The biological content of the model is well-supported by the literature:

  1. The TIGIT-PVR interaction as an inhibitory axis in NK cells is accurately depicted, consistent with the PMID:23154388 study which demonstrates that this interaction "suppresses granule polarization and cytotoxicity of NK cells."

  2. The recruitment of Grb2 (P62993) by TIGIT as a molecular adaptor is correctly represented, as the literature shows the ITT-like motif of TIGIT is phosphorylated at Tyr225 and binds to Grb2.

  3. The subsequent recruitment of SHIP1 (INPP5D/Q92835) through Grb2 and its inositol-polyphosphate 5-phosphatase activity is correctly depicted as the mechanism that prematurely terminates PI3K signaling.

  4. The inclusion of PIK3CB (P42338) and its 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity in natural killer cell mediated cytotoxicity is well-supported by PMID:36248894.

Model Structure and Connectivity

The causal flow of the model follows this pathway: 1. PVR (P15151) provides receptor ligand activity (GO:0048018) that directly positively regulates TIGIT (Q495A1) signaling receptor activity (GO:0038023) 2. TIGIT signaling receptor activity directly positively regulates GRB2 (P62993) protein-macromolecule adaptor activity (GO:0030674) 3. GRB2 adaptor activity directly positively regulates INPP5D/SHIP1 (Q92835) inositol-polyphosphate 5-phosphatase activity (GO:0004445) 4. INPP5D/SHIP1 directly negatively regulates PIK3CB (P42338) 1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity (GO:0046934)

This causal chain correctly represents the negative regulation of PI3K-mediated NK cell cytotoxicity by the TIGIT-PVR interaction.

Ontology and Evidence Usage

The model appropriately uses: - Molecular functions from GO (e.g., receptor ligand activity, signaling receptor activity) - Cellular locations (plasma membrane, cytoplasm) - Proper causal relationships (directly positively regulates, directly negatively regulates) - Evidence codes with proper literature citations (ECO:0000314 - direct assay evidence used in manual assertion)

Compliance with GO-CAM Guidelines

The model follows GO-CAM practices: 1. Each activity is properly connected in a causal chain 2. Entities are appropriately enabled by the correct gene products 3. Cellular locations are specified for each activity 4. Activities are part of appropriate biological processes 5. Each assertion has evidence with appropriate citations

Specific Improvements or Suggestions

  1. Complex Representation: While the model doesn't explicitly represent complexes, this follows GO-CAM guidelines as each protein's individual molecular function is known and represented. According to the document "How to annotate complexes in GO-CAM", this is the correct approach when the subunits carrying specific activities are known.

  2. Activity Completeness: The model could be expanded to represent additional downstream effectors of the PI3K pathway in NK cells or additional regulatory interactions of SHIP1.

  3. Evidence Diversity: While the model uses appropriate direct evidence, it could be strengthened by including additional supporting evidence from more publications.

Conclusion

This GO-CAM model (gomodel:66b5638000001968) effectively represents the TIGIT-PVR inhibitory signaling pathway in NK cells with accurate biological content, proper causal connectivity, and appropriate use of GO terms and evidence. The model clearly captures how PVR binding to TIGIT initiates a signaling cascade that recruits Grb2 and SHIP1, ultimately inhibiting PI3K activity and suppressing NK cell cytotoxicity.

The model is parsimonious and well-structured, making it easy to understand the inhibitory pathway involved in natural killer cell-mediated cytotoxicity regulation. It properly implements GO-CAM curation best practices and effectively represents the biological mechanism described in the literature.