ArticleCellular & molecular biology letters2026
Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA.
Article in Cellular & molecular biology letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundEffectors of the vertebrate Hedgehog (HH) signaling pathway are organized within primary cilia (PC). Protein kinase A (PKA), a ubiquitously distributed kinase in most cells, functions as a specific negative regulator of the HH pathway. Its functional specificity in the HH pathway has been suggested to be controlled by cyclic adenosine monophosphate (cAMP) in PC. However, the regulation of PKA and its roles in PC remain unclear, partly owing to the lack of observations regarding PKA localization in PC during the resting state of HH signaling, as well as conflicting reports on the dynamic changes in ciliary cAMP levels and HH pathway activity. Here, we clarify that PKA with basal activity in PC specifically regulates the HH pathway and confirm that Smoothened (SMO)-mediated HH pathway activation may not be fully dependent on its inhibition of ciliary PKA activity.
methodsTo investigate the role of PKA during HH pathway, we have developed an improved ciliary-localized Förster resonance energy transfer (FRET)-based A-kinase activity probe (Nphp3N-AKAR2-CR) for real-time monitoring of ciliary PKA activity in both cultured cells and living embryos. Additionally, by leveraging a highly efficient ciliary targeting peptide (Nphp3N), we specifically delivered PKA variants to either PC or cytoplasm, thereby dissecting the regulatory roles of PKA in the HH pathway across different subcellular compartments. Furthermore, we performed constitutively active SMO variant (SMOA1)–forskolin (FSK) titration assays to validate the dose-dependent relationship underlying SMO-mediated inhibition of PKA.
resultsBasal ciliary PKA activity in cells was detected by this probe, despite the absence of observable PKA catalytic subunits in PC. Only ciliary-targeted PKA can modulate the HH pathway, even when PC integrity is disrupted. Notably, ciliary PKA activity is barely changed by either inhibition or activation of the HH pathway at the level of SMO. Furthermore, even low concentrations of FSK efficiently inhibit the HH pathway in the presence of SMOA1.
conclusionsA basal level of PKA localized in PC but not cytoplasm specifically regulates HH signal transduction, and SMO-mediated activation of the HH pathway may not be solely attributed to the direct regulation of ciliary PKA activity.
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