14-3-3epsilon
D. melanogaster
14-3-3epsilon
What the model saw
Gene: 14-3-3epsilon Organism: Drosophila melanogaster Known functions: 14-3-3epsilon. molecular sequestering activity. phosphoserine residue binding. protein binding. protein heterodimerization activity. transcription coactivator binding.
View unredacted entry
14-3-3epsilon. molecular sequestering activity. phosphoserine residue binding. protein binding. protein heterodimerization activity. transcription coactivator binding.
Solver output
14-3-3 proteins are central regulators of the insulin/IGF-1 signaling (IIS) and TOR pathways, which are the primary nutrient-sensing axes governing longevity in Drosophila. Through phosphoserine residue binding and molecular sequestering activity, 14-3-3epsilon retains key signaling molecules (e.g., FOXO transcription factor, Raf, and other kinase substrates) in the cytoplasm or modulates their activity, thereby fine-tuning IIS output. In Drosophila, 14-3-3epsilon (encoded by leonardo/14-3-3ε) acts as a negative regulator of IIS by sequestering components that would otherwise promote growth and suppress stress-response programs. Reduced IIS signaling via 14-3-3-mediated sequestration of pathway activators is well-established to extend lifespan in flies. Additionally, its protein heterodimerization and transcription coactivator binding activities allow it to modulate transcriptional programs linked to stress resistance and longevity downstream of FOXO.
GenAge curators classify each gene's normal function as promoting (Pro-Longevity) or opposing (Anti-Longevity) longevity, based on synthesis across studies. Loss-of-function effects can vary from this depending on the manipulation.
Advisor judgment
The model predicted "pro_longevity" but the ground truth is "anti_longevity." The model constructed a plausible-sounding but ultimately incorrect mechanistic narrative. While 14-3-3 proteins do interact with IIS/FOXO pathways, the model's reasoning that 14-3-3epsilon acts as a negative regulator of IIS (thereby extending lifespan) is backwards from the actual finding. In reality, 14-3-3epsilon is anti-longevity in Drosophila, meaning its activity promotes aging rather than extending lifespan. The model was moderately confident (0.72) in its wrong answer. The mechanistic reasoning about FOXO sequestration and IIS modulation was speculative and led to the wrong conclusion about the direction of effect.
Raw API responses
solver
{
"reasoning": "14-3-3 proteins are central regulators of the insulin/IGF-1 signaling (IIS) and TOR pathways, which are the primary nutrient-sensing axes governing longevity in Drosophila. Through phosphoserine residue binding and molecular sequestering activity, 14-3-3epsilon retains key signaling molecules (e.g., FOXO transcription factor, Raf, and other kinase substrates) in the cytoplasm or modulates their activity, thereby fine-tuning IIS output. In Drosophila, 14-3-3epsilon (encoded by leonardo/14-3-3ε) acts as a negative regulator of IIS by sequestering components that would otherwise promote growth and suppress stress-response programs. Reduced IIS signaling via 14-3-3-mediated sequestration of pathway activators is well-established to extend lifespan in flies. Additionally, its protein heterodimerization and transcription coactivator binding activities allow it to modulate transcriptional programs linked to stress resistance and longevity downstream of FOXO.",
"confidence": 0.72,
"key_pathways": [
"insulin/IGF-1 signaling (IIS) pathway",
"FOXO transcription factor regulation",
"TOR nutrient-sensing pathway"
],
"mechanism_class": "deregulated_nutrient_sensing",
"longevity_influence": "pro_longevity"
}advisor
{
"notes": "The model predicted \"pro_longevity\" but the ground truth is \"anti_longevity.\" The model constructed a plausible-sounding but ultimately incorrect mechanistic narrative. While 14-3-3 proteins do interact with IIS/FOXO pathways, the model's reasoning that 14-3-3epsilon acts as a negative regulator of IIS (thereby extending lifespan) is backwards from the actual finding. In reality, 14-3-3epsilon is anti-longevity in Drosophila, meaning its activity promotes aging rather than extending lifespan. The model was moderately confident (0.72) in its wrong answer. The mechanistic reasoning about FOXO sequestration and IIS modulation was speculative and led to the wrong conclusion about the direction of effect.",
"failure_mode": "confident_wrong",
"answer_correct": false,
"mechanism_correct": false,
"reasoning_quality": 2,
"ground_truth_questionable": false
}