Role of G-protein-coupled receptor kinase 2 in the «Drosophila» Hedgehog Signaling Pathway
Bibliographic record
Abstract
The Hedgehog (Hh) signaling pathway is an essential and highly conserved pathway required for embryonic development and adult tissues homeostasis in both invertebrates and vertebrates. In humans, abnormal Hh signaling leads to numerous congenital diseases and deregulation of Hh signaling is associated with certain aspects of tumorigenesis. Therefore, a complete characterization of this pathway may help us to better understand the role of Hh signaling under physiological and pathological conditions. A key transducer of Hh signaling is Smoothened (Smo), a seven-pass transmembrane protein and distant member of the G-protein-coupled receptor (GPCR) family. In the absence of the secreted Hh protein, Smo is inhibited by another membrane protein, the Hh-receptor Patched (Ptc). Hh binding to Ptc releases this inhibition and triggers accumulation of Smo at the cell surface. Phosphorylation of Smo by Protein kinase A (PKA) and additional kinases allows Smo to adopt an active conformation, which turns the Hh signaling pathway on and ultimately allows the expression of Hh target genes. G-protein-coupled receptor kinases (GRKs) are known to phosphorylate active GPCRs and promote homologous desensitization of GPCR signaling. Smo is a functional GPCR in Drosophila and several recent studies suggest that GRKs participate in Hh signaling in both invertebrates and vertebrates. To address the role of GRKs in Drosophila Hh signaling, we analyzed flies mutant for gprk2, one of two GRKs in flies. Interestingly, gprk2 mutant flies display defects typical of impaired Hh signaling, suggesting that Gprk2 is required for transducing the Hh signal. Further studies, however, showed that Gprk2 also plays a negative role in Hh signaling by promoting Smo desensitization, which is consistent with typical GRK biology. To explain the dual and contradictory role of Gprk2 in Hh signaling, we hypothesized that heterotrimeric G-protein-dependent signaling may be affected in gprk2 mutants through misregulation of Smo and other GPCRs. Consistent with this idea we find that basal cAMP levels are abnormally low in gprk2 mutants. Cellular cAMP concentrations control the activity of PKA, the key activator of Smo. With genetic experiments, we confirmed that cAMP levels and PKA activity are limiting for Hh target gene expression in gprk2 mutants. In conclusion, our results suggest that Gprk2 regulates Hh signaling in two ways. On one hand, it limits Hh signaling by promoting homologous desensitization of Smo. On the other hand, it is also required to keep cellular cAMP concentrations in a physiological range that is required for normal Hh signaling. We speculate that the abnormally low cAMP levels in gprk2 mutants are not only caused by misregulation of Smo, but also by a more global misregulation of GPCR signaling, suggesting that Hh signalling is affected by signalling cross-talk.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 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) | 0.001 | 0.001 |
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".