Differential Binding of GIGYF1 and GIGYF2 to GRB10 in Humans: Implications for Insulin and IGF-1 Signaling
Bibliographic record
Abstract
Cognitive impairment associated with insulin and insulin-like growth factor 1 (IGF-1) resistance represents a significant and escalating public health concern, particularly in the context of the rising prevalence of Type 2 diabetes (T2D).This resistance is intricately linked to neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD), all of which are projected to increase in incidence.Central to these conditions is the dysfunction of insulin receptor (ISR) and IGF-1 receptor (IGF-1R) signaling pathways in the brain, leading to disruptions in downstream cascades like PI3K/AKT and Ras/MAPK.These disruptions impair critical cellular functions, including glucose transport, due to the mislocalization of the GLUT4 transporter.In murine models, three key proteins-Growth factor receptor-bound protein 10 (GRB10), and GRB10interacting GYF proteins 1 and 2 (GIGYF1 and GIGYF2)-have been identified as negative regulators of ISR and IGF-1R signaling.GRB10 directly binds to phosphorylated tyrosine residues on these receptors, attenuating signal transduction.GIGYF1 and GIGYF2, initially discovered through yeast two-hybrid assays as GRB10 interactors, are known to inhibit translation initiation via 4EHP-dependent and -independent mechanisms.In mice, these proteins interact with GRB10 through a conserved PPGF motif, a feature not present in other species.Furthermore, GIGYF1 and GIGYF2 have been implicated in the endosomal retention of ISR and IGF-1R, preventing their recycling to the cell surface and thereby exacerbating insulin resistance.Notably, GIGYF1 has been associated with ASD, GIGYF2 with PD, and GRB10 with AD.This study aims to elucidate the conservation and functional relevance of the GRB10-GIGYF1/2 interaction in humans.Through a series of binding affinity and in vitro assays, we demonstrate that, unlike in mice, human GIGYF2 does not interact with GRB10, while GIGYF1 retains this Table of Contents
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".