ArticlePLoS genetics2014
A broadly conserved g-protein-coupled receptor kinase phosphorylation mechanism controls Drosophila smoothened activity.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
- Convergent mechanisms in Wnt and Hedgehog signaling.Science signaling · 2026Review
- A Structure-Guided Kinase-Transcription Factor Interactome Atlas Reveals Docking Landscapes of the Kinome.bioRxiv : the preprint server for biology · 2025Article
- Tai/NCOA2 suppresses the Hedgehog pathway by directly targeting the transcription factor Ci/GLI.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits.PLoS biology · 2021Article
- Extensive crosstalk of G protein-coupled receptors with the Hedgehog signalling pathway.Development (Cambridge, England) · 2021Article
- Competition between two phosphatases fine-tunes Hedgehog signaling.The Journal of cell biology · 2021Article
- Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.EMBO molecular medicine · 2020Article
- Article
- Regulation of the RNA-binding protein Smaug by the GPCR Smoothened via the kinase Fused.EMBO reports · 2020Article
- Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction.Scientific reports · 2019Article
- Smoothened-dependent and -independent pathways in mammalian noncanonical Hedgehog signaling.The Journal of biological chemistry · 2019Article
- Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy.Cancers · 2019Review
- Review
- Activation of Smoothened in the Hedgehog pathway unexpectedly increases GαThe Journal of biological chemistry · 2018Article
- G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts.Journal of molecular and cellular cardiology · 2018Article
- The emerging roles of phosphatases in Hedgehog pathway.Cell communication and signaling : CCS · 2017Review
- Regulation of Hedgehog Signalling Inside and Outside the Cell.Journal of developmental biology · 2016Article
- Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.PLoS biology · 2016Article
- An essential role for Grk2 in Hedgehog signalling downstream of Smoothened.EMBO reports · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Hedgehog (Hh) signaling is essential for normal growth, patterning, and homeostasis of many tissues in diverse organisms, and is misregulated in a variety of diseases including cancer. Cytoplasmic Hedgehog signaling is activated by multisite phosphorylation of the seven-pass transmembrane protein Smoothened (Smo) in its cytoplasmic C-terminus. Aside from a short membrane-proximal stretch, the sequence of the C-terminus is highly divergent in different phyla, and the evidence suggests that the precise mechanism of Smo activation and transduction of the signal to downstream effectors also differs. To clarify the conserved role of G-protein-coupled receptor kinases (GRKs) in Smo regulation, we mapped four clusters of phosphorylation sites in the membrane-proximal C-terminus of Drosophila Smo that are phosphorylated by Gprk2, one of the two fly GRKs. Phosphorylation at these sites enhances Smo dimerization and increases but is not essential for Smo activity. Three of these clusters overlap with regulatory phosphorylation sites in mouse Smo and are highly conserved throughout the bilaterian lineages, suggesting that they serve a common function. Consistent with this, we find that a C-terminally truncated form of Drosophila Smo consisting of just the highly conserved core, including Gprk2 regulatory sites, can recruit the downstream effector Costal-2 and activate target gene expression, in a Gprk2-dependent manner. These results indicate that GRK phosphorylation in the membrane proximal C-terminus is an evolutionarily ancient mechanism of Smo regulation, and point to a higher degree of similarity in the regulation and signaling mechanisms of bilaterian Smo proteins than has previously been recognized.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.