PXD023893-2

PXD023893 is an original dataset announced via ProteomeXchange.

Title	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.
HostingRepository	PanoramaPublic
AnnounceDate	2021-04-25
AnnouncementXML	Submission_2021-04-25_06:29:34.506.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Ruth Huttenhain
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Phospho; Carbamidomethyl; Oxidation
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-29 16:14:51	ID requested
1	2021-03-10 12:18:59	announced
⏵ 2	2021-04-25 06:29:35	announced	: Added publication

Arveseth CD, Happ JT, Hedeen DS, Zhu JF, Capener JL, Klatt Shaw D, Deshpande I, Liang J, Xu J, Stubben SL, Nelson IB, Walker MF, Kawakami K, Inoue A, Krogan NJ, Grunwald DJ, H, ü, ttenhain R, Manglik A, Myers BR, Smoothened transduces Hedgehog signals via activity-dependent sequestration of PKA catalytic subunits. PLoS Biol, 19(4):e3001191(2021) [pubmed]

submitter keyword: PRM, Phosphorylation, Smoothened

Ruth Huttenhain
contact affiliation	UCSF
contact email	ruth.huttenhain@ucsf.edu
lab head
Ruth Huttenhain
contact affiliation	UCSF
contact email	ruth.huttenhain@ucsf.edu
dataset submitter

Panorama Public dataset URI