ArticleProceedings of the National Academy of Sciences of the United States of America2004
Extensive phosphorylation of Smoothened in Hedgehog pathway activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 181 citations in OpenAlex.
- GRAMD1/ASTER-mediated cholesterol transport promotes Smoothened cholesterylation at the endoplasmic reticulum.The EMBO journal · 2023Article
- Gotta Go Slow: Two Evolutionarily Distinct Annelids Retain a Common Hedgehog Pathway Composition, Outlining Its Pan-Bilaterian Core.International journal of molecular sciences · 2022Article
- Hedgehog signaling mechanism and role in cancer.Seminars in cancer biology · 2022Review
- Article
- Arih2 regulates Hedgehog signaling through smoothened ubiquitylation and ER-associated degradation.Journal of cell science · 2022Article
- The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulateseLife · 2022Article
- Characterization of Smoothened Phosphorylation and Activation.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Review
- Membrane potential regulates Hedgehog signalling in the Drosophila wing imaginal disc.EMBO reports · 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
- 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
- Phosphoproteomics of short-term hedgehog signaling in human medulloblastoma cells.Cell communication and signaling : CCS · 2020Article
- DUBs Activating the Hedgehog Signaling Pathway: A Promising Therapeutic Target in Cancer.Cancers · 2020Review
- Bi-allelic Variations of SMO in Humans Cause a Broad Spectrum of Developmental Anomalies Due to Abnormal Hedgehog Signaling.American journal of human genetics · 2020Article
- Proteostasis in the Hedgehog signaling pathway.Seminars in cell & developmental biology · 2019Review
- Generating and working with Drosophila cell cultures: Current challenges and opportunities.Wiley interdisciplinary reviews. Developmental biology · 2019Review
- Patched1-ArhGAP36-PKA-Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The transmembrane protein Smoothened (Smo) is activated in response to the extracellular protein signal, Hedgehog (Hh), and transmits this state of pathway activity into the cell. Previous studies in Drosophila have correlated pathway activation with Smo accumulation and increased phosphorylation. Using immunopurification and mass spectrometry, we identify here 26 serine/threonine residues within the Smo C-terminal cytoplasmic tail that are phosphorylated in Hh-stimulated cells. By systematically substituting alanine or glutamic acid to block or simulate phosphorylation, we provide evidence for a functional role of collective phosphorylation of a subset of phosphoresidues in pathway activation. This role is indicated by the ability of altered Smo proteins to produce changes in transcription of Hh-responsive genes in vivo and in cultured cells. These altered Smo proteins also affect biochemical indicators of pathway activity, such as Smo accumulation and phosphorylation of other pathway components. The prevalence and arrangement of phosphoresidues within the Smo cytoplasmic tail at recognition sites for cAMP-dependent protein kinase and casein kinase 1 suggest a role for these kinases in Smo phosphorylation, and such a role is supported by the effects of manipulating kinase activities in cultured cells. Our studies confirm and extend previous studies showing a positive effect for cAMP-dependent protein kinase and uncover a positive role for casein kinase 1alpha in Hh pathway activation.
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Registered trials
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.