ArticleScience signaling2011
Sequential phosphorylation of smoothened transduces graded hedgehog signaling.
Article in Science signaling, 2011. 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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Who cites it
41 citing papers in PubMed.
- Gene model for the ortholog ofmicroPublication biology · 2025Article
- Non-canonical non-genomic morphogen signaling in anucleate platelets: a critical determinant of prothrombotic function in circulation.Cell communication and signaling : CCS · 2024Review
- Gotta Go Slow: Two Evolutionarily Distinct Annelids Retain a Common Hedgehog Pathway Composition, Outlining Its Pan-Bilaterian Core.International journal of molecular sciences · 2022Article
- Article
- Dissection of the microRNA Network Regulating Hedgehog Signaling inFrontiers in cell and developmental biology · 2022Article
- Functional requirements of protein kinases and phosphatases in the development of the Drosophila melanogaster wing.G3 (Bethesda, Md.) · 2021Article
- Review
- Review
- 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
- Phosphorylation and Ubiquitylation Regulate Protein Trafficking, Signaling, and the Biogenesis of Primary Cilia.Frontiers in cell and developmental biology · 2021Review
- Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.EMBO molecular medicine · 2020Article
- Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused.Cell death & disease · 2020Article
- Regulation of the RNA-binding protein Smaug by the GPCR Smoothened via the kinase Fused.EMBO reports · 2020Article
- Investigation of Isoform Specific Functions of the V-ATPase a Subunit DuringFrontiers in genetics · 2020Article
- Proteostasis in the Hedgehog signaling pathway.Seminars in cell & developmental biology · 2019Review
- Biochemical mechanisms of vertebrate hedgehog signaling.Development (Cambridge, England) · 2019Review
- Synaptojanin regulates Hedgehog signalling by modulating phosphatidylinositol 4-phosphate levels.Journal of biosciences · 2018Article
- Article
- The emerging roles of phosphatases in Hedgehog pathway.Cell communication and signaling : CCS · 2017Review
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The correct interpretation of a gradient of the morphogen Hedgehog (Hh) during development requires phosphorylation of the Hh signaling activator Smoothened (Smo); however, the molecular mechanism by which Smo transduces graded Hh signaling is not well understood. We show that regulation of the phosphorylation status of Smo by distinct phosphatases at specific phosphorylated residues creates differential thresholds of Hh signaling. Phosphorylation of Smo was initiated by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and further enhanced by casein kinase I (CKI). We found that protein phosphatase 1 (PP1) directly dephosphorylated PKA-phosphorylated Smo to reduce signaling mediated by intermediate concentrations of Hh, whereas PP2A specifically dephosphorylated PKA-primed, CKI-phosphorylated Smo to restrict signaling by high concentrations of Hh. We also established a functional link between sequentially phosphorylated Smo species and graded Hh activity. Thus, we propose a sequential phosphorylation model in which precise interpretation of morphogen concentration can be achieved upon versatile phosphatase-mediated regulation of the phosphorylation status of an essential activator in developmental signaling.
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