Characterization of the Physiological Role of PDZ-RhoGEF in Drosophila and Mice
Bibliographic record
Abstract
Biological outputs of insulin/IGF signaling are regulated through essential mediators, such as IRSs, PI3-kinase, and PKB/Akt. These mediators serve critical roles in signal propagation, feedback, and as junctions for crosstalk with other pathways. Abnormal insulin/IGF signaling results in disease, such as obesity, diabetes, and cancer. Given the vital role of this signaling pathway to human health, unraveling its regulatory mechanisms is crucial. Components of this pathway are highly conserved throughout evolution. PTEN, one of the well-defined regulators of this pathway, functions as a lipid phosphatase that negatively regulates insulin/IGF-1 signaling at the PIP3 level, a phosphoinositol that is upregulated by activated PI3-kinase in both Drosophila and mammals. To discover genetic modulators of PTEN in Drosophila, we performed a loss-of-function genetic screen to identify molecules that modify the phenotype elicited by PTEN overexpression in the Drosophila eye. From this screen, we identified a member of the Dbl-family, the guanine nucleotide exchange factor DRhoGEF2, which suppresses the PTEN-overexpression eye phenotype via its effects on dPKB/dAkt activation. By conducting a genetic rescue, we established that PDZ-RhoGEF, a member of the regulator of G-protein signal (RGS)-like domain containing Rho GEFs (RGS-RhoGEFs) subfamily of Dbl-family GEFs, is the mammalian counterpart of DRhoGEF2. PDZ-RhoGEF is essential for cell proliferation and survival through ROCK-dependent activation of IRS/PI3-kinase signaling cascade, which has a major impact on adipose tissue homeostasis. Through an integrative approach, we have demonstrated that DRhoGEF2/PDZ-RhoGEF-dependent signaling has tissue-specific effects on insulin/IGF-signaling throughput in both Drosophila and mammals. Particularly, we have demonstrated the role played by PDZ-RhoGEF in diet related pathology, provides an alternative therapeutic opportunity in disease intervention.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".