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Now that I have a good understanding of the model and the relevant GO-CAM guidelines, I'll proceed with my review of the GO-CAM model "Thrombospondin-1/CD36 inhibition of angiogenesis in endothelial cells (Human)" (gomodel:65d7e4ac00001282).

GO-CAM Model Review: Thrombospondin-1/CD36 inhibition of angiogenesis in endothelial cells (Human)

Model Overview

Model ID: gomodel:65d7e4ac00001282
Title: Thrombospondin-1/CD36 inhibition of angiogenesis in endothelial cells (Human)
Taxon: Human (NCBITaxon:9606)
Status: Production

Model Description

This model represents a signaling pathway by which thrombospondin-1 (THBS1) inhibits angiogenesis in endothelial cells through interactions with CD36, leading to downstream activation of protein tyrosine phosphatase SHP-1 (PTPN6), which in turn negatively regulates vascular endothelial growth factor receptor 2 (KDR/VEGFR2).

Components and Activities

The model includes four key proteins and their activities:

  1. THBS1 (UniProtKB:P07996) - Extracellular matrix structural constituent
  2. CD36 (UniProtKB:P16671) - Thrombospondin receptor activity
  3. PTPN6/SHP-1 (UniProtKB:P29350) - Protein tyrosine phosphatase activity
  4. KDR/VEGFR2 (UniProtKB:P35968) - Vascular endothelial growth factor receptor activity

Pathway Flow Analysis

The causal flow in the model is:

  1. THBS1 (extracellular matrix structural constituent) → directly positively regulates → CD36 (thrombospondin receptor activity)
  2. CD36 (thrombospondin receptor activity) → directly positively regulates → PTPN6 (protein tyrosine phosphatase activity)
  3. PTPN6 (protein tyrosine phosphatase activity) → directly negatively regulates → KDR (vascular endothelial growth factor receptor activity)

This represents a cascade where THBS1 in the extracellular matrix binds to CD36 on the plasma membrane, activating CD36's receptor activity, which then activates PTPN6's phosphatase activity, leading to the dephosphorylation and inhibition of KDR/VEGFR2.

Biological Processes

  • THBS1, CD36, and PTPN6 activities are part of negative regulation of angiogenesis (GO:0016525)
  • KDR activity is part of positive regulation of angiogenesis (GO:0045766)

This correctly shows the antagonistic relationship between these two pathways - THBS1/CD36/PTPN6 inhibit angiogenesis, while KDR/VEGFR2 promotes it.

Cellular Localization

  • THBS1 occurs in extracellular matrix (GO:0031012)
  • CD36 and KDR occur in plasma membrane (GO:0005886)
  • PTPN6 occurs in plasma membrane (GO:0005886)

Evidence Assessment

The model uses appropriate evidence codes and references:

  • Direct assay evidence (ECO:0000314) from PMID:10102632, PMID:23896411, PMID:9245797, PMID:6341993
  • Mutant phenotype evidence (ECO:0000315) from PMID:17562706
  • Automatically integrated combinatorial evidence (ECO:0000245) from PMID:23979707

QC Assessment

Strengths

  1. The model correctly represents the inhibitory pathway from THBS1 to VEGFR2
  2. Appropriate causal relationships are used (directly positively regulates, directly negatively regulates)
  3. Correct cellular compartments are assigned
  4. Evidence is provided with appropriate PMIDs and evidence codes

Potential issues

  1. Subcellular Location of PTPN6/SHP-1: According to the UniProt entry, PTPN6 is primarily cytoplasmic and nuclear. The model places it at the plasma membrane. While PTPN6 can be recruited to the plasma membrane upon CD36 stimulation, it would be more accurate to indicate its primary location as cytoplasm.

  2. Biological Process Assignment: All activities except KDR are annotated to negative regulation of angiogenesis (GO:0016525). This seems correct based on the literature, but it would be helpful to include more specific processes for each component if available (e.g., signal transduction processes).

  3. Missing Intermediate Steps: The literature suggests that the pathway from CD36 to KDR inhibition involves additional kinases and signaling intermediates like src-family kinases. These are not represented in the model, which simplifies the pathway.

  4. Cellular Context Specification: The model mentions endothelial cells in the title, but the ZFA:0009065 (endothelial cell) term is in the objects list but not explicitly used in the annotations. It would be helpful to make this cellular context more explicit.

Recommendations for Improvement

  1. Update PTPN6 subcellular location: Consider changing the subcellular location of PTPN6 to cytoplasm as its primary location, with a note that it can be recruited to the membrane upon CD36 activation.

  2. Add intermediate signaling components: If supported by the literature, consider adding intermediate signaling components between CD36 and PTPN6, such as src-family kinases that are known to be involved in this pathway.

  3. Specify cell type: Explicitly annotate the activities to occur in endothelial cells using the existing term ZFA:0009065.

  4. Expand biological process annotations: Consider adding more specific biological process terms for each component to better represent their specific roles in the signaling pathway.

  5. Consider additional VEGFR2 regulation details: If available in the literature, add details about how PTPN6 regulates VEGFR2, such as which tyrosine residues are dephosphorylated.

Conclusion

Overall, this is a well-constructed GO-CAM model that accurately represents the inhibitory pathway from THBS1 to VEGFR2 via CD36 and PTPN6. The model follows GO-CAM best practices for representing signaling receptor activities and inhibitory pathways. With a few minor adjustments as suggested above, the model would provide an even more comprehensive representation of this important anti-angiogenic pathway.

The model is consistent with current literature on thrombospondin-1 as an inhibitor of angiogenesis, CD36 as its receptor, and the downstream inhibition of VEGFR2 signaling. The connections between components follow GO-CAM guidelines for representing signaling pathways.