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Now that I have reviewed the GO-CAM model and related proteins, I'll provide a detailed review of the model.

Review of GO-CAM Model: CD28/GRB2 axis leading to RAS activation (Human)

Model Overview

This GO-CAM model (gomodel:662af8fa00002332) represents the CD28/GRB2 axis that leads to RAS activation in human T cells. The model describes the signaling pathway initiated by CD80/CD86 binding to CD28, which triggers a cascade through GRB2 adaptor recruitment leading to activation of guanyl-nucleotide exchange factors (GEFs) such as VAV1 and SOS1.

Biological Accuracy Assessment

The model accurately represents the well-established CD28 co-stimulatory pathway that is critical for T cell activation. Key features include:

  1. Receptor-Ligand Interactions: The model correctly shows that both CD80 (P33681) and CD86 (P42081) function as receptor ligands that positively regulate CD28's coreceptor activity. This is consistent with literature showing these molecules are primary costimulatory ligands for CD28.

  2. CD28 Signaling: CD28 (P10747) is appropriately annotated with coreceptor activity (GO:0015026) and is shown to directly positively regulate GRB2 (P62993), which is supported by multiple studies (including PMID:9784967).

  3. GRB2 Adaptor Function: GRB2 is correctly annotated with molecular adaptor activity (GO:0030674), which is its primary function in signaling cascades as documented in UniProt.

  4. GEF Activation: The model shows GRB2 directly positively regulating both VAV1 (P15498) and SOS1 (Q07889), which are both annotated with guanyl-nucleotide exchange factor activity (GO:0005085). This is consistent with the established role of GRB2 in recruiting these GEFs during T cell activation.

Structure and Connectivity

The model has a clear and logical flow with appropriate causal relationships:

  1. The causal relationships use proper RO terms (RO:0002629 "directly positively regulates") to connect activities.

  2. All activities are connected in a biologically meaningful way that reflects the signaling flow from cell surface receptors (CD80/CD86) to CD28 to GRB2 to downstream GEFs.

  3. Each protein's activity is appropriately localized: CD80, CD86, and CD28 at the plasma membrane (GO:0005886), while GRB2, VAV1, and SOS1 in the cytoplasm (GO:0005737).

  4. All activities are correctly placed in the context of T cell activation (GO:0042110) or T cell costimulation (GO:0031295) biological processes.

Evidence Support

The model includes appropriate evidence for each assertion:

  1. Most relationships are supported by experimental evidence codes such as ECO:0000314 (direct assay evidence) or ECO:0000304 (author statement supported by traceable reference).

  2. Key references include PMID:24845157 for CD80/CD86-CD28 interactions and PMID:7539782 for CD28-GRB2-GEF connections.

  3. All assertions include appropriate provenance information.

Areas for Improvement

While the model is generally well-constructed, I've identified a few areas that could be enhanced:

  1. Pathway Completion: The model stops at the GEF activities of VAV1 and SOS1. It could be extended to show activation of small GTPases (RAS/RAC) and subsequent MAPK cascade activation, which would complete the signaling pathway to its nuclear effects.

  2. Detailed Mechanism for CD28-GRB2 Interaction: The model could be enhanced by including the phosphorylation step of CD28 at Tyr-191, which creates the binding site for GRB2's SH2 domain. This is a critical mechanistic detail for this pathway as documented in UniProt (PMID:7568038).

  3. PI3K Pathway Branch: The model currently focuses on the RAS activation branch of CD28 signaling. Adding the parallel PI3K pathway (which is also activated by CD28-GRB2 interactions) would provide a more complete picture of CD28 costimulation effects.

Compliance with GO-CAM Best Practices

The model follows GO-CAM best practices in several ways:

  1. It uses the appropriate molecular function terms for each protein.

  2. Activities are properly connected using recommended causal relationship terms.

  3. Activities are appropriately contextualized with cellular component terms.

  4. Each assertion is supported by appropriate evidence.

  5. The model follows the GO-CAM guidance for representing signaling pathways, particularly in how it handles adaptor proteins like GRB2.

Conclusion

The GO-CAM model (gomodel:662af8fa00002332) accurately represents the CD28/GRB2 axis leading to RAS activation in human T cells. It successfully captures the key steps in this important co-stimulatory pathway and adheres to GO-CAM best practices. The model could be enhanced by extending it to include downstream effects and by adding more mechanistic details about protein interactions, particularly the phosphorylation-dependent recruitment of GRB2 to CD28.

The model provides a valuable resource for understanding T cell costimulation through CD28 and how it leads to activation of guanyl-nucleotide exchange factors that ultimately activate RAS signaling.