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Based on all the information collected, I'll now review the GO-CAM model (gomodel:66187e4700002778) that represents the reelin signaling pathway in human.

Review of GO-CAM Model 66187e4700002778: The reelin signaling pathway (Human)

Model Overview

This GO-CAM model (gomodel:66187e4700002778) represents the reelin signaling pathway in humans. The model includes the following key players: - RELN (Reelin, UniProtKB:P78509) - LRP8 (ApoER2, UniProtKB:Q14114-4) - DAB1 (Disabled homolog 1, UniProtKB:O75553) - FYN (Tyrosine-protein kinase Fyn, UniProtKB:P06241)

The model captures the causal relationships between these proteins in the canonical reelin signaling pathway.

Model Accuracy and Completeness

Components and Activities

The model correctly identifies the core components of the reelin signaling pathway:

  1. RELN (Reelin): Represented with receptor ligand activity (GO:0048018), which is appropriate given its role as a secreted glycoprotein that binds to receptors.

  2. LRP8 (ApoER2): Represented with reelin receptor activity (GO:0038025), which is appropriate as LRP8 is one of the primary receptors for reelin.

  3. FYN: Represented with protein tyrosine kinase activity (GO:0004713), which is correct as Fyn is a tyrosine kinase that phosphorylates DAB1.

  4. DAB1: Represented with signaling adaptor activity (GO:0035591), which is appropriate as DAB1 is an adapter protein that mediates the reelin signaling cascade.

Causal Relationships

The model correctly represents the following causal relationships: - RELN directly positively regulates LRP8 (RO:0002629) - LRP8 directly positively regulates FYN (RO:0002629) - FYN directly positively regulates DAB1 (RO:0002629)

These relationships accurately reflect the canonical reelin signaling pathway where reelin binds to its receptors (LRP8/ApoER2), leading to activation of Fyn kinase, which then phosphorylates DAB1.

Cellular Locations

The model correctly annotates the cellular locations of the proteins: - RELN in extracellular space (GO:0005615) - LRP8 in plasma membrane (GO:0005886) - DAB1 in cytoplasm (GO:0005737)

These localizations are consistent with the known biology of these proteins.

Quality Issues and Recommendations

1. Missing Component: VLDLR

The model lacks the very low-density lipoprotein receptor (VLDLR), which is another important receptor for reelin alongside LRP8. The PMID:30873003 paper clearly demonstrates that both ApoER2 (LRP8) and VLDLR are involved in reelin signaling and both can mediate Dab1 phosphorylation. Genetic experiments have shown that only the double knockout of both receptors recapitulates the full "reeler phenotype" (Trommsdorff et al.), whereas loss of either receptor alone produces distinctive phenotypes on their own.

Recommendation: Add VLDLR to the model with reelin receptor activity (GO:0038025) and show it being regulated by RELN similarly to LRP8.

2. Receptor Oligomerization

As demonstrated in PMID:30873003, both LRP8 (ApoER2) and VLDLR form homo-oligomers in the absence of reelin, and full-length reelin increases the size of these clusters, which is critical for signaling. The model does not capture this clustering behavior.

Recommendation: Consider adding appropriate annotations to capture the oligomerization of receptors and how this is enhanced by reelin binding.

3. Phosphorylation of DAB1

The model correctly shows FYN acting on DAB1, but it doesn't specifically capture the phosphorylation event. The PMID:16979591 and other references clearly show that Fyn phosphorylates DAB1 at specific tyrosine residues, which is a critical event in the signaling cascade.

Recommendation: Explicitly annotate the phosphorylation of DAB1 by FYN, possibly using a more specific GO term for the activity.

4. Biological Process Annotations

While the model correctly includes the reelin-mediated signaling pathway (GO:0038026) as a biological process, it could benefit from additional biological process annotations that capture the downstream effects of this pathway, such as neuronal migration or layer formation in the cerebral cortex.

Recommendation: Add additional biological process terms to capture the downstream effects of reelin signaling, such as "layer formation in cerebral cortex" (GO:0021819).

5. Evidence Codes

The model uses ECO:0000250 (sequence similarity evidence used in manual assertion) and ECO:0000314 (direct assay evidence used in manual assertion) as evidence codes, which are appropriate. However, for some assertions, more specific evidence could be provided, especially from human studies where available.

Recommendation: Ensure all assertions have appropriate evidence codes and citations, preferably from human studies when available.

Conclusion

The GO-CAM model gomodel:66187e4700002778 provides a good representation of the core components and causal relationships in the reelin signaling pathway in humans. However, it could be improved by adding VLDLR as another reelin receptor, capturing receptor oligomerization, explicitly annotating the phosphorylation of DAB1, adding more specific biological process annotations, and ensuring all assertions have appropriate evidence.

Overall, the model is scientifically sound but would benefit from these enhancements to provide a more complete and detailed representation of reelin signaling.