PXD019346

PXD019346 is an original dataset announced via ProteomeXchange.

Title	Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Subunits
Description	The Hedgehog (Hh) pathway is essential for tissue homeostasis, and misregulation 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 2 (GRK2)-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 vertebrate Hh signal transduction at the membrane to transcription factor activation in the nucleus. In contrast to existing models, our work shows that this aspect of Hh signaling is fundamentally similar between species. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades.
HostingRepository	PRIDE
AnnounceDate	2021-04-26
AnnouncementXML	Submission_2021-04-25_21:51:06.868.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ruth Huttenhain
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-22 03:25:04	ID requested
1	2021-04-24 22:06:51	announced
⏵ 2	2021-04-25 21:51:07	announced	2021-04-26: Updated project metadata.

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]

10.1371/JOURNAL.PBIO.3001191;

submitter keyword: Smoothened, Phosphorylation

Ruth Huttenhain
contact affiliation	Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
contact email	ruth.huttenhain@ucsf.edu
lab head
Ruth Huttenhain
contact affiliation	UCSF
contact email	ruth.huttenhain@ucsf.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/04/PXD019346

PRIDE project URI

• PRIDE
  1. PXD019346
     1. Label: PRIDE project
     2. Name: Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Subunits