PXD004810-1

PXD004810 is an original dataset announced via ProteomeXchange.

Title	Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy
Description	Project Description(50 to 5000 characters):Phospholamban (PLN) plays a central role in Ca2+ homeostasis in cardiac myocytes through its regulation of the SERCA2A Ca2+ pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in both humans and transgenic mice, but the downstream signaling defects leading to heart failure are poorly understood. Here, we used precision tandem mass spectrometry to gain unbiased insights into the global phosphorylation dynamics of 2041 cardiac phosphoproteins in early affected heart tissue in the transgenic R9C mouse model of DCM compared to wild type littermates. 251 dysregulated phosphorylation sites were quantified after affinity capture and identification of 4337 phosphopeptides from fractionated whole heart homogenates. Enrichment analysis of the differential phosphoprotein patterns revealed dozens of signaling pathways regulating cardiovascular activity that are selectively impaired in early stages of DCM. Strikingly, dysregulated signaling through the Notch-1 receptor, recently linked to cardiomyogenesis and embryonic cardiac stem cell development and differentiation but never directly implicated in DCM before, was one of the most prominently perturbed pathways. We verified dysregulation of Notch1 downstream components in early symptomatic R9C transgenic mouse hearts compared to wild type by immunoblot analysis and confocal immunofluorescence microscopy. These data reveal unexpected connections between protein kinases, cell signaling networks and downstream effectors essential for proper cardiac function
HostingRepository	PRIDE
AnnounceDate	2016-12-12
AnnouncementXML	Submission_2016-12-12_13:05:07.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sadhna Phanse
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2016-08-15 06:43:39	ID requested
⏵ 1	2016-12-12 13:05:08	announced
2	2017-10-24 02:18:44	announced	Updated project metadata.

Kuzmanov U, Guo H, Buchsbaum D, Cosme J, Abbasi C, Isserlin R, Sharma P, Gramolini AO, Emili A, Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy. Proc Natl Acad Sci U S A, 113(44):12592-12597(2016) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: phosphoproteomics, dialted cardiomyopathy, signaling pathways, Notch, heart failure

Andrew Emili
contact affiliation	Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto ON M5S 3E1, Canada
contact email	andrew.emili@utoronto.ca
lab head
Sadhna Phanse
contact affiliation	University of Toronto
contact email	sadhna.phanse@utoronto.ca
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/2016/12/PXD004810

PRIDE project URI

• PRIDE
  1. PXD004810
     1. Label: PRIDE project
     2. Name: Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy