ArticleNature2008
G protein Galphai functions immediately downstream of Smoothened in Hedgehog signalling.
Article in Nature, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.
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Who cites it
124 citing papers in PubMed, 200 citations in OpenAlex.
- Smoothened and ciliary GPCRs regulate ciliary protein kinase A activity involved in Hedgehog signal transduction.PLoS biology · 2026Article
- Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA.Cellular & molecular biology letters · 2026Article
- The highly expressedJournal of gastrointestinal oncology · 2025Article
- Proximity based proteomics reveals Git1 as a regulator of Smoothened signaling.bioRxiv : the preprint server for biology · 2025Article
- A Novel Variant in the Cyto-Tail ofMolecular syndromology · 2024Article
- Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.The Journal of cell biology · 2024Article
- GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.Nature structural & molecular biology · 2024Article
- Article
- Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies.Signal transduction and targeted therapy · 2023Review
- HIB/SPOP inhibits Ci/Gli-mediated tumorigenesis by modulating the RNA Polymerase II components stabilities.iScience · 2023Article
- GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway.bioRxiv : the preprint server for biology · 2023Article
- Activation mechanism of the human Smoothened receptor.Biophysical journal · 2023Article
- Cholesterol and Phosphoinositides in Cilia Biology.Advances in experimental medicine and biology · 2023Review
- Hedgehog signaling mechanism and role in cancer.Seminars in cancer biology · 2022Review
- Novel de novo pathogenic variant in the GNAI1 gene as a cause of severe disorders of intellectual development.Journal of human genetics · 2022Article
- Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.Science China. Life sciences · 2022Review
- TMED2 binding restricts SMO to the ER and Golgi compartments.PLoS biology · 2022Article
- Cholesterylation of Smoothened is a calcium-accelerated autoreaction involving an intramolecular ester intermediate.Cell research · 2022Article
- Measuring Smoothened (SMO)-Mediated Activation of the GMethods in molecular biology (Clifton, N.J.) · 2022Article
- Gli Phosphorylation Code in Hedgehog Signal Transduction.Frontiers in cell and developmental biology · 2022Review
64 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The hedgehog (Hh) signalling pathway has an evolutionarily conserved role in patterning fields of cells during metazoan development, and is inappropriately activated in cancer. Hh pathway activity is absolutely dependent on signalling by the seven-transmembrane protein smoothened (Smo), which is regulated by the Hh receptor patched (Ptc). Smo signals to an intracellular multi-protein complex containing the Kinesin related protein Costal2 (Cos2), the protein kinase Fused (Fu) and the transcription factor Cubitus interruptus (Ci). In the absence of Hh, this complex regulates the cleavage of full-length Ci to a truncated repressor protein, Ci75, in a process that is dependent on the proteasome and priming phosphorylations by Protein kinase A (PKA). Binding of Hh to Ptc blocks Ptc-mediated Smo inhibition, allowing Smo to signal to the intracellular components to attenuate Ci cleavage. Because of its homology with the Frizzled family of G-protein-coupled receptors (GPCR), a likely candidate for an immediate Smo effector would be a heterotrimeric G protein. However, the role that G proteins may have in Hh signal transduction is unclear and quite controversial, which has led to widespread speculation that Smo signals through a variety of novel G-protein-independent mechanisms. Here we present in vitro and in vivo evidence in Drosophila that Smo activates a G protein to modulate intracellular cyclic AMP levels in response to Hh. Our results demonstrate that Smo functions as a canonical GPCR, which signals through Galphai to regulate 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.