PXD064187-1

PXD064187 is an original dataset announced via ProteomeXchange.

Title	PhosphoproteomPhosphoproteomics Maps the Calcineurin-NFAT-DSCR1.4 Signaling as Druggable Axis in Gαq-R183Q–Driven Capillary Malformationsics
Description	Vascular malformations are congenital lesions caused by somatic and germline mutations that disrupt developmental signaling pathways. Capillary malformations (CMs) typically present as port-wine stains in the skin and can also affect ocular and cerebral tissues in Sturge Weber Syndrome (SWS), leading to aesthetic, neurological, and ophthalmic complications. CMs are caused by a somatic mosaic mutation in the GNAQ gene in endothelial cells, leading to an activating p.R183Q substitution in the Gαq protein. The underlying mechanisms of Gαq-R183Q-driven CMs formation still remain unclear. To address this, we generated CRISPR/Cas9-engineered human dermal microvascular endothelial cells lacking endogenous Gαq, whilst expressing the Gαq-R183Q mutant instead. The Gαq-R183Q mutation strongly impaired endothelial cell migration and angiogenic sprouting capacity compared to wild-type controls. Next, using SILAC-based quantitative proteomics, we investigated the Gαq-R183Q-induced changes in the endothelial phosphoproteome. These analyses revealed prominent activation of calcineurin-NFAT signaling pathway in Gαq-R183Q-expressing endothelial cells, leading to dephosphorylation of NFAT1 and NFAT2 and the selective expression of their transcriptional target DSCR1.4. Immunofluorescence of patient-derived skin biopsies confirmed deregulation of NFAT1/2 and the expression of DSRC1 in endothelial cells, validating their potential importance in CMs. We further demonstrate that pharmacological inhibition of calcineurin with tacrolimus (FK506) could partially restore NFAT signaling, collective cell migration and sprouting in Gαq-R183Q endothelial cells. Intriguingly, the genetic depletion of the NFAT target DSCR1 in Gαq-R183Q cells fully rescued calcineurin/NFAT signaling as well as key endothelial functions. In summary, we uncovered a calcineurin-NFAT-DSCR1.4 signal transduction axis that is driven by Gαq-R183Q and established its importance for endothelial angiogenic properties. These findings highlight that calcineurin/NFAT signaling represents a promising therapeutic target to restore endothelial function in CMs.
HostingRepository	PRIDE
AnnounceDate	2026-02-04
AnnouncementXML	Submission_2026-02-04_06:41:52.931.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Harmjan Vos
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-22 04:07:34	ID requested
⏵ 1	2026-02-04 06:41:53	announced

10.1007/S10456-026-10029-9;

submitter keyword: tacrolimus.,Sturge-Weber Syndrome, angiogenesis, endothelial cell, GNAQ p.R183Q, migration, capillary malformation

Stephan Huveneers
contact affiliation	Amsterdam UMC, University of Amsterdam, Department of Medical Biochemistry, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
contact email	s.huveneers@amsterdamumc.nl
lab head
Harmjan Vos
contact affiliation	University Medical Center Utrecht Dept. Molecular Cancer Research
contact email	h.r.vos-3@umcutrecht.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD064187
     1. Label: PRIDE project
     2. Name: PhosphoproteomPhosphoproteomics Maps the Calcineurin-NFAT-DSCR1.4 Signaling as Druggable Axis in Gαq-R183Q–Driven Capillary Malformationsics