Vertebrate cells differentially interpret ciliary and extraciliary cAMP

Truong, Melissa E.; Bilekova, Sara; Choksi, Semil P.; Li, Wan; Bugaj, Lukasz J.; Xu, Ke; Reiter, Jeremy F.

doi:10.1016/j.cell.2021.04.002

Cited by 87 publications

(125 citation statements)

References 106 publications

(121 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another limitation of any approach that perturbs subcellular pools of cAMP, be it through genetic, optogenetic or chemogenetic means (Guo et al, 2019;Hansen et al, 2020;Truong et al, 2021), arises from the cilioplasm not being isolated from the cytoplasm. The second messengers, cAMP and Ca 2+ , are both freely diffusible between ciliary and extraciliary compartments (Delling et al, 2016;Truong et al, 2021). Therefore, extraciliary cAMP could diffuse into ciliary compartments and vice versa.…”

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

“…However, the concentrations achieved from such leaks might not reach critical thresholds required for downstream PKA signaling at cilia (Truong et al, 2021).…”

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

“…A recent study used elegant optogenetic methods regulating subcellular cAMP levels and genetic approaches subcellularly expressing dominant negative PKA to perturb Shhmediated somite patterning in zebrafish (Truong et al, 2021). They showed that ciliary, but not cytoplasmic, production of cAMP functions through PKA localized in cilia to repress Shhmediated somite patterning.…”

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

“…The PKA regulatory subunit RI and RII localizes to cilia (Bachmann et al, 2016;Mick et al, 2015) and centrosomes (Barzi et al, 2010;Saade et al, 2017;Tuson et al, 2011), respectively. PKA-c also localizes to centrosomes (Barzi et al, 2010;Saade et al, 2017;Tuson et al, 2011) and cilia (Arveseth et al, 2021;Truong et al, 2021). Gpr161 is the only GPCR known to be an AKAP.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Hwang

Somatilaka

White

et al. 2021

eLife

View full text Add to dashboard Cite

The role of compartmentalized signaling in primary cilia during tissue morphogenesis is not well understood. The cilia-localized G-protein-coupled receptor—Gpr161 represses hedgehog pathway via cAMP signaling. We engineered a knock-in at Gpr161 locus in mice to generate a variant (Gpr161mut1), which was ciliary localization defective but cAMP signaling competent. Tissue phenotypes from hedgehog signaling depend on downstream bifunctional Gli transcriptional factors functioning as activators/repressors. Compared to knockout (ko), Gpr161mut1/ko had delayed embryonic lethality, moderately increased hedgehog targets and partially down-regulated Gli3-repressor. Unlike ko, the Gpr161mut1/ko neural tube did not show Gli2-activator-dependent expansion of ventral-most progenitors. Instead, the intermediate neural tube showed progenitor expansion that depends on loss of Gli3-repressor. Increased extraciliary receptor (Gpr161mut1/mut1) prevented ventralization. Morphogenesis in limb buds and midface requires Gli-repressor; these tissues in Gpr161mut1/mut1 manifested hedgehog hyperactivation phenotypes—polydactyly and midfacial widening. Thus, ciliary and extraciliary Gpr161 pools likely establish tissue-specific Gli-repressor thresholds in determining morpho-phenotypic outcomes.

show abstract

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

“…However, the concentrations achieved from such leaks might not reach critical thresholds required for downstream PKA signaling at cilia (Truong et al, 2021).…”

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

Section: Limitations Of the Gpr161 Mut1 Allelementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Hwang

Somatilaka

White

et al. 2021

eLife

View full text Add to dashboard Cite

show abstract

“…Interestingly, Gpr161 C-tail has been proposed to be an A-kinase anchoring protein (AKAP) for PKA activation in cilia by binding to type I PKA regulatory subunits (Bachmann et al, 2016). The PKA regulatory subunit RIa and RII localizes to cilia (Bachmann et al, 2016;Mick et al, 2015) and centrosomes (Barzi et al, 2010;Saade et al, 2017;Tuson et al, 2011), respectively, whereas PKA-c localizes to centrosomes (Barzi et al, 2010;Saade et al, 2017;Tuson et al, 2011) and cilia (Truong et al, 2021). Gpr161 is the only GPCR known to be an AKAP.…”

Section: Introductionmentioning

confidence: 99%

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Hwang

Somatilaka

White

et al. 2021

Preprint

View full text Add to dashboard Cite

The primary cilium localized G-protein-coupled receptor Gpr161 represses hedgehog pathway via cAMP signaling in multiple tissues. However, whether Gpr161 functions exclusively from inside cilia is unclear. Here, we generated ciliary localization-defective but cAMP signaling-competent Gpr161mut1 knock-in mice. We uncovered distinctive roles for subcellular Gpr161 pools, contingent upon dependence of the morpho-phenotypic spectrum on downstream Gli transcriptional regulators. Compared to Gpr161 knockout, gene dosage of the Gpr161mut1 allele caused delayed embryonic lethality, reduced upregulation of hedgehog targets and intermediate Gli3 repressor levels. Unlike Gpr161 knockout with aberrant ventral progenitor expansion in neural tube, extraciliary Gpr161 pools in Gpr161mut1 prevented Gli2 activator-mediated ventralization. However, limb buds and midfacial tissues that require Gli repressor for morphogenesis, showed polydactyly and midface widening in Gpr161mut1 from hyperactivation. Thus, Gpr161 ciliary and extraciliary pools functioned as rheostats preventing gradations of hedgehog pathway hyperactivation. Ciliary Gpr161 pools prevented tissue-specific phenotypes dependent specifically on reduced Gli repressor thresholds.

show abstract

Nanomediator–Effector Cascade Systems for Amplified Protein Kinase Activity Imaging and Phosphorylation‐Induced Drug Release In Vivo

et al. 2021

View full text Add to dashboard Cite

Protein kinases constitute arich pool of biomarkers and therapeutic targets of tremendous diseases including cancer.H owever,s ensing kinase activity in vivo while implementing treatments according to kinase hyperactivation remains challenging.H erein, we present an anomediator-effector cascade system that can in situ magnify the subtle events of kinase-catalyzed phosphorylation via DNAa mplification machinery to achieve kinase activity imaging and kinaseresponsive drug release in vivo.Inthis cascade,the phosphorylation-mediated disassembly of DNA/peptide complex on the nanomediators initiated the detachment of fluorescent hairpin DNAs from the nanoeffectors via hybridization chain reaction (HCR), leading to fluorescence recovery and therapeutic cargo release.W edemonstrated that this nanosystem simultaneously enabled trace protein kinase A(PKA) activity imaging and ondemand drug delivery for inhibition of tumor cell growth both in vitro and in vivo,affording akinase-specific sense-and-treat paradigm for cancer theranostics.

show abstract

Vertebrate cells differentially interpret ciliary and extraciliary cAMP

Cited by 87 publications

References 106 publications

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Ciliary and extraciliary Gpr161 pools repress hedgehog signaling in a tissue-specific manner

Nanomediator–Effector Cascade Systems for Amplified Protein Kinase Activity Imaging and Phosphorylation‐Induced Drug Release In Vivo

Contact Info

Product

Resources

About