ArticlePLoS biology2021
Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits.
Article in PLoS biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 64 citations in OpenAlex.
- Therapeutic potential of astrocyte transdifferentiated neurons.Neural regeneration research · 2026Article
- Convergent mechanisms in Wnt and Hedgehog signaling.Science signaling · 2026Review
- Hypervariable loop profiling decodes sequence determinants of antibody stability.Nature structural & molecular biology · 2026Article
- Smoothened and ciliary GPCRs regulate ciliary protein kinase A activity involved in Hedgehog signal transduction.PLoS biology · 2026Article
- Structural mechanism for noncanonical GPCR signaling in the Hedgehog pathway.Nature structural & molecular biology · 2026Article
- Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA.Cellular & molecular biology letters · 2026Article
- Trisomy 21 alters ciliary localization of Sonic Hedgehog signaling proteins.bioRxiv : the preprint server for biology · 2026Article
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- Caudal fin shape imprinted during late zebrafish embryogenesis is re-patterned by the Sonic hedgehog pathway.PLoS biology · 2025Article
- Hedgehog pathway, cell cycle, and primary cilium.Cell death discovery · 2025Review
- Hedgehog-stimulated phosphorylation at multiple sites activates Ci by altering Ci-Ci interfaces without full Suppressor of Fused dissociation.PLoS biology · 2025Article
- Physiological analysis of the mechanism of Ci transcription factor activation through multiple Fused phosphorylation sites in Hedgehog signal transduction.bioRxiv : the preprint server for biology · 2025Article
- Proximity based proteomics reveals Git1 as a regulator of Smoothened signaling.bioRxiv : the preprint server for biology · 2025Article
- Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer.bioRxiv : the preprint server for biology · 2024Article
- Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.The Journal of cell biology · 2024Article
- A simple and scalable zebrafish model of Sonic hedgehog medulloblastoma.Cell reports · 2024Article
- GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.PLoS biology · 2024Article
- Emerging mechanistic understanding of cilia function in cellular signalling.Nature reviews. Molecular cell biology · 2024Review
- Numb positively regulates Hedgehog signaling at the ciliary pocket.Nature communications · 2024Article
- Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation.eLife · 2023Article
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 2 countries.
Funding
Abstract
The Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here, we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase (GRK)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.
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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.