PXD030888

PXD030888 is an original dataset announced via ProteomeXchange.

Title	Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome C4PR_LIV
Description	Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushing’s syndrome. We define mechanisms of action for the PKAcL205R and W196R variants. Proximity proteomic techniques demonstrate that both Cushing’s mutants are excluded from A kinase anchoring protein (AKAP) signaling islands, whereas live-cell photoactivation microscopy reveals that these kinase mutants indiscriminately diffuse throughout the cell. Only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate PKAc mutants into AKAP complexes abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Analyses of adrenal-specific PKAc-W196R knock-in mice and Cushing’s syndrome patient tissue reveal defective signaling mechanisms of the disease. Surprisingly each Cushing’s mutant engages a different mitogenic signaling pathway, with upregulation of YAP/TAZ by PKAc-L205R and ERK kinase activation by PKAc-W196R. Thus, aberrant spatiotemporal regulation of each Cushing’s variant promotes the transmission of distinct downstream pathogenic signals.
HostingRepository	PRIDE
AnnounceDate	2022-07-12
AnnouncementXML	Submission_2022-07-12_07:50:54.007.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030888
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	leonard daly
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-11 01:33:45	ID requested
⏵ 1	2022-07-12 07:50:54	announced

Dataset with its publication pending

submitter keyword: cortisol, PRKACA, adrenal, stress hormone, anchoring, signaling, proximity biotinylation, photoactivation, scaffold

Claire Eyers
contact affiliation	University of Liverpool
contact email	ceyers@liverpool.ac.uk
lab head
leonard daly
contact affiliation	University of Liverpool
contact email	leonard.daly@liverpool.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030888
     1. Label: PRIDE project
     2. Name: Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing’s syndrome C4PR_LIV