Skip to content

Based on my review of the GO-CAM model and associated documents, I'll now provide a comprehensive evaluation of model gomodel:65bc474400000537 "Regulation of Hippo signaling by MAP4K4 (Human)."

Review of GO-CAM Model: Regulation of Hippo signaling by MAP4K4 (Human)

gomodel:65bc474400000537

Model Overview

This model captures the regulation of Hippo signaling pathway in humans with a particular focus on MAP4K4's role. The model represents how MAP4K4 and other kinases act in parallel to MST1/2 to activate LATS1/2, which ultimately regulates the transcriptional coactivators YAP1 and WWTR1/TAZ.

Biological Content Assessment

Accuracy of Biological Content

The model accurately reflects the current understanding of the Hippo signaling pathway based on the cited literature. The key findings from PMID:35429439 and PMID:26437443 describing how MAP4K4 functions in parallel to MST1/2 to activate LATS1/2 are well represented. The model correctly captures the phosphorylation events where LATS1/2 phosphorylates and inhibits YAP1/TAZ, preventing their nuclear translocation and transcriptional coactivator functions.

Completeness of Pathway Representation

The model includes the core components of the Hippo pathway from upstream kinases (MST1/2, MAP4K4) through the central LATS1/2 kinases to the downstream effectors (YAP1 and WWTR1). The causal relationships showing regulation of nuclear transcriptional coactivators are appropriate.

Evidence Support

All activities in the model are well supported by primary literature evidence, with appropriate ECO codes (ECO:0000314 - direct assay evidence used in manual assertion) and PMID citations. The model references key papers including PMID:35429439, PMID:26437443, and PMID:15688006.

Technical Assessment

GO-CAM Best Practices

The model follows GO-CAM best practices for representing kinase activities and transcriptional coregulation:

  1. Protein kinase activities: The model correctly represents protein serine/threonine kinase activities (GO:0004674) for LATS1, LATS2, STK3, STK4, and MAP4K4, consistent with their established functions.

  2. Transcriptional coregulator activities: YAP1 and WWTR1 are correctly annotated with transcription coregulator activity (GO:0003712) in the nucleus, following the guidelines in the "Transcription coregulator activity" document.

  3. Causal relationships: The model uses appropriate causal relationship predicates:

  4. RO:0002630 (directly negatively regulates) for LATS1/2 regulating YAP1/WWTR1
  5. RO:0002629 (directly positively regulates) for upstream kinases activating LATS1/2

  6. RO:0002413 (provides input for) where appropriate

  7. Cellular locations: Activities are appropriately contextualized with cellular locations, with kinase activities occurring in the cytoplasm (GO:0005737) and transcriptional activities in the nucleus (GO:0005634).

Areas for Improvement

  1. Comment clarification: The model includes a comment stating "The regulation has been capture for MAP4k4 because it is the one used for experimental evidences but according to KO, at least MAP4K1, MAP4K2, MAP4K6 and MAP4K7 are also able to regulate the hippo signaling." This is accurate based on PMID:26437443, but it might be clearer to reword this as "MAP4K4 has been featured as the primary regulator in this model based on experimental evidence, but knockout studies indicate that MAP4K1, MAP4K2, MAP4K6, and MAP4K7 can also regulate Hippo signaling."

  2. Missing link detail: In one of the causal associations for LATS1's activity (65bc474400000651), there's a redundant causal association with no evidence: 

    "causal_associations":[
   {"type":"CausalAssociation","evidence":[],"predicate":"RO:0002629","downstream_activity":"gomodel:65bc474400000537/65bc474400000586"}
]
    This appears to be a duplicate of the properly evidenced association above it.

  3. Potential for expansion: Given PMID:26437443 demonstrates the redundancy and parallel functions of multiple MAP4K family members, an expanded version of this model might represent the other MAP4K family members (MAP4K1/2/6/7) more explicitly, though I recognize the curator has acknowledged this in the comment.

Conclusion

This GO-CAM model is a high-quality representation of the regulation of Hippo signaling by MAP4K4 and other kinases. The biological content is accurate, evidence-based, and follows GO-CAM best practices for representing signaling pathways. The model effectively captures the parallel pathways of MAP4K4 and MST1/2 in activating LATS1/2, which subsequently regulates YAP1 and WWTR1 transcriptional coactivator activities.

The minor issue with a redundant unevidenced causal association is the only technical flaw in an otherwise excellent model.

Recommendation

The model is suitable for production status with only minor clarifications suggested for the comment text and removal of the redundant unevidenced causal association.