ArticlePLoS biology2016
Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.
Article in PLoS biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
41 citing papers in PubMed.
- Convergent mechanisms in Wnt and Hedgehog signaling.Science signaling · 2026Review
- Multifaceted role of primary cilia and ciliary proteins: A potential nexus for hedgehog signaling and prostate cancer.Biochimica et biophysica acta. Molecular basis of disease · 2026Review
- Integrated Phosphoproteomics Identifies TGFβ-Dependent Phosphorylation Events Linking Kinase Signaling to Autophagy in Palatogenesis.Proteomes · 2026Article
- Identification of New Ciliary Signaling Pathways in the Brain and Insights into Neurological Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.PLoS biology · 2024Article
- CD56 polysialylation promotes the tumorigenesis and progression via the Hedgehog and Wnt/β-catenin signaling pathways in clear cell renal cell carcinoma.Cancer cell international · 2023Article
- Casein kinase 1 gamma regulates oxidative stress response via interacting with the NADPH dual oxidase complex.PLoS genetics · 2023Article
- From mesenchymal niches to engineeredMaterials today. Bio · 2022Article
- Dose-dependent phosphorylation and activation of Hh pathway transcription factors.Life science alliance · 2022Article
- Hedgehog signaling mechanism and role in cancer.Seminars in cancer biology · 2022Review
- Article
- The crosstalk between long non-coding RNAs and the hedgehog signaling pathway in cancer.Medical oncology (Northwood, London, England) · 2022Review
- Regulation of PDF receptor signaling controlling daily locomotor rhythms in Drosophila.PLoS genetics · 2022Article
- Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review.Cellular and molecular life sciences : CMLS · 2022Review
- Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.Science China. Life sciences · 2022Review
- Cell-Based Assays for Smoothened Ubiquitination and Sumoylation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Characterization of Smoothened Phosphorylation and Activation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Regulation of Smoothened Trafficking and Abundance in Hedgehog Signaling.Frontiers in cell and developmental biology · 2022Review
- Regulation of Hedgehog Signal Transduction by Ubiquitination and Deubiquitination.International journal of molecular sciences · 2021Review
- Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.
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