{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Arveseth CD"],"funding":["NICHD NIH HHS","NCI NIH HHS","National Institutes of Health","National Institute of General Medical Sciences","NIGMS NIH HHS","Defense Sciences Office, DARPA"],"pagination":["e3001191"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8096101"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["19(4)"],"pubmed_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."],"journal":["PLoS biology"],"pubmed_title":["Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits."],"pmcid":["PMC8096101"],"funding_grant_id":["P30 CA042014","R35 GM133672","T32HD007491","HR0011-19-2-0020, HR001119S0092-FP-FP-002","1R35GM133672","T32 HD007491"],"pubmed_authors":["Nelson IB","Capener JL","Krogan NJ","Stubben SL","Kawakami K","Hedeen DS","Huttenhain R","Walker MF","Xu J","Happ JT","Inoue A","Grunwald DJ","Zhu JF","Liang J","Myers BR","Klatt Shaw D","Manglik A","Arveseth CD","Deshpande I"],"additional_accession":[]},"is_claimable":false,"name":"Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Apr","modification":"2026-05-08T06:42:58.38Z","creation":"2025-04-05T10:29:25.392Z"},"accession":"S-EPMC8096101","cross_references":{"pubmed":["33886552"],"doi":["10.1371/journal.pbio.3001191"]}}