ArticlePLoS biology2024
GRK2 kinases in the primary cilium initiate SMOOTHENED-PKA signaling in the Hedgehog cascade.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Recent advances in the development of GRK2 inhibitors: blocking the interaction of GRK2 with its partners.Acta pharmacologica Sinica · 2026Review
- Primary cilia: master conductors of cellular communication in development and disease.Nature reviews. Nephrology · 2026Review
- Convergent mechanisms in Wnt and Hedgehog signaling.Science signaling · 2026Review
- Primary cilia and neural computation.Journal of biomedical science · 2026Review
- Smoothened and ciliary GPCRs regulate ciliary protein kinase A activity involved in Hedgehog signal transduction.PLoS biology · 2026Article
- Hypervariable loop profiling decodes sequence determinants of antibody stability.Nature structural & molecular biology · 2026Article
- Light- and chemical-induced ciliary signaling governs dorsal/ventral regionalization of human telencephalic organoids.Nature communications · 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
- Development of a Chemical Probe to Enable Characterization of the Casein Kinase 1γ Subfamily.Journal of medicinal chemistry · 2026Article
- Trisomy 21 alters ciliary localization of Sonic Hedgehog signaling proteins.bioRxiv : the preprint server for biology · 2026Article
- Regulation of G protein-coupled receptor kinase 2 and its role in tumors.Journal of translational medicine · 2026Review
- Development of a chemical probe to enable characterization of the casein kinase 1γ subfamily.bioRxiv : the preprint server for biology · 2025Article
- G Protein-Coupled Receptor Signal Intersection at the Primary Cilium.BioEssays : news and reviews in molecular, cellular and developmental biology · 2025Review
- CCDC66 regulation of cytoskeleton and cilia stability is important for signaling and epithelial organization.PLoS biology · 2025Article
- Proximity based proteomics reveals Git1 as a regulator of Smoothened signaling.bioRxiv : the preprint server for biology · 2025Article
- A simple and scalable zebrafish model of Sonic hedgehog medulloblastoma.Cell reports · 2024Article
- Emerging mechanistic understanding of cilia function in cellular signalling.Nature reviews. Molecular cell biology · 2024Review
- Immunomodulatory potential of primary cilia in the skin.Frontiers in immunology · 2024Review
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Abstract
During Hedgehog (Hh) signal transduction in development and disease, the atypical G protein-coupled receptor (GPCR) SMOOTHENED (SMO) communicates with GLI transcription factors by binding the protein kinase A catalytic subunit (PKA-C) and physically blocking its enzymatic activity. Here, we show that GPCR kinase 2 (GRK2) orchestrates this process during endogenous mouse and zebrafish Hh pathway activation in the primary cilium. Upon SMO activation, GRK2 rapidly relocalizes from the ciliary base to the shaft, triggering SMO phosphorylation and PKA-C interaction. Reconstitution studies reveal that GRK2 phosphorylation enables active SMO to bind PKA-C directly. Lastly, the SMO-GRK2-PKA pathway underlies Hh signal transduction in a range of cellular and in vivo models. Thus, GRK2 phosphorylation of ciliary SMO and the ensuing PKA-C binding and inactivation are critical initiating events for the intracellular steps in Hh signaling. More broadly, our study suggests an expanded role for GRKs in enabling direct GPCR interactions with diverse intracellular effectors.
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