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65d7e4ac00000082 DUSP22 inhibition of TCR signaling via UBR2 inhibition Human

Now I'll review the GO-CAM model in detail.

GO-CAM Review: DUSP22 inhibition of TCR signaling via UBR2 inhibition (Human)

Model ID: gomodel:65d7e4ac00000082

Summary of the Model

This GO-CAM model describes the molecular pathway of DUSP22-mediated inhibition of T-cell receptor (TCR) signaling through the regulation of UBR2 activity, which in turn affects Lck activity. The model captures several key molecular interactions and activities:

  1. DUSP22 (Q9NRW4) has protein tyrosine/serine/threonine phosphatase activity
  2. BTRC/β-TrCP (Q9Y297) functions as a ubiquitin-like ligase-substrate adaptor
  3. UBR2 (Q8IWV8) has ubiquitin protein ligase activity
  4. Lck (P06239) has protein tyrosine kinase activity

The causal relationships between these activities show how DUSP22 provides input for BTRC, which leads to UBR2 degradation via K48-linked ubiquitination, ultimately inhibiting Lck's K63-linked ubiquitination and activation in TCR signaling.

Detailed Review

Biological Content Assessment

The biological content of the model accurately reflects the findings in the recent publication by Shih et al. (2024) [PMID:38225265]. The model correctly depicts:

  1. DUSP22's role as a negative regulator of T-cell receptor signaling by dephosphorylating UBR2
  2. BTRC (β-TrCP) serving as a ubiquitin ligase-substrate adaptor for UBR2
  3. UBR2's function in promoting K63-linked ubiquitination of Lck
  4. Lck's role in TCR signaling pathway

The molecular functions and biological processes assigned to each protein are consistent with the literature and correctly connected via appropriate causal relationships.

GO Terms and Annotation Consistency

The model uses appropriate GO terms for molecular functions and biological processes:

  • DUSP22: Protein tyrosine/serine/threonine phosphatase activity (GO:0008138) - appropriate given DUSP22's dual specificity
  • BTRC: Ubiquitin-like ligase-substrate adaptor activity (GO:1990756) - correct for its role in the SCF complex
  • UBR2: Ubiquitin protein ligase activity (GO:0061630) - appropriate for its E3 ligase function
  • Lck: Protein tyrosine kinase activity (GO:0004713) - correct for its role in phosphorylating TCR components

The biological processes are also correctly assigned: - DUSP22 is part of negative regulation of T cell receptor signaling pathway (GO:0050860) - BTRC is part of protein K48-linked ubiquitination (GO:0070936) - UBR2 is part of protein K63-linked ubiquitination (GO:0070534) - Lck is part of T cell receptor signaling pathway (GO:0050852)

Causal Relationships

The causal relationships in the model are properly defined and follow GO-CAM guidelines:

  1. DUSP22 provides input for (RO:0002413) BTRC - correctly indicates that DUSP22 dephosphorylates UBR2, making it a substrate for BTRC
  2. BTRC regulates UBR2 by using a non-direct "regulates" relationship (RO:0002409) - This is marked as regulation but per the E3 ubiquitin ligases guideline, it should ideally be "directly regulates" since it's targeting UBR2 for degradation
  3. UBR2 directly positively regulates (RO:0002629) Lck - correctly shows that UBR2 ubiquitinates and activates Lck

Cellular Components

The cellular locations are appropriately specified: - DUSP22 located in plasma membrane (GO:0005886) - BTRC located in cytoplasm (GO:0005737) - UBR2 located in cytoplasm (GO:0005737) - Lck located in plasma membrane (GO:0005886)

These locations align with the known distribution of these proteins during TCR signaling.

Evidence Consistency

The evidence codes and citations are correctly used: - Direct assay evidence (ECO:0000314) is cited for most of the molecular functions and causal relationships - Curator inference (ECO:0000305) is used appropriately for some cellular locations - The recent publication (PMID:38225265) is correctly cited for the UBR2-Lck relationship - Historical literature references for Lck's role in TCR signaling are also correctly cited (PMID:214242, PMID:12150984, PMID:8943371)

Improvement Suggestions

  1. Causal relationship refinement: The causal relationship between BTRC and UBR2 uses "regulates" (RO:0002409), but according to the E3 ubiquitin ligases guideline, when an adaptor protein like BTRC is targeting a protein for degradation, "directly regulates" would be more appropriate.

  2. Model expansion opportunity: The model could potentially be expanded to include:

  3. The SCF complex scaffold (CUL1) which works with BTRC to form a functional E3 ligase complex
  4. The downstream effects of Lck activation on TCR signaling (e.g., ZAP70 phosphorylation)

  5. The specific phosphatase activity of DUSP22 on UBR2 at Ser1694 and Tyr1697 residues

  6. Evidence detail: Some evidence annotations could potentially be enhanced with more specific experimental details from the primary literature.

Conclusion

This GO-CAM model (gomodel:65d7e4ac00000082) provides an accurate representation of the DUSP22-UBR2-Lck regulatory pathway in T-cell receptor signaling, as recently described in the literature. The model effectively captures the key molecular activities, subcellular locations, and causal relationships among these proteins.

The model follows GO-CAM curation guidelines for representing E3 ubiquitin ligase activities and complexes. It is biologically sound, well-supported by evidence, and properly constructed according to GO-CAM standards.

With minor refinements to the causal relationship between BTRC and UBR2, and potential expansions to include additional components of the pathway, this model will provide an even more comprehensive representation of this important regulatory mechanism in T-cell biology.