| Title: |
Calcineurin-NFAT-DSCR1.4 signaling as druggable axis in Gαq-R183Q-driven capillary malformations |
| Authors: |
Xu,Tong; Janssen,Vera; Reinhard,Nathalie R; Sobrevals-Alcaraz, Paula; van Es, Robert M; de Haan,Annett; de Swart,Julian; Wehrens,Martijn; de Kraker,Hannah; Wolkerstorfer,Albert; van der Horst,Chantal M A M; Vos, Harmjan R; Huveneers,Stephan; CMM Groep Burgering; Cancer |
| Publication Year: |
2026 |
| Subject Terms: |
Calcineurin/metabolism; Capillaries/abnormalities; Endothelial Cells/metabolism; GTP-Binding Protein alpha Subunits; Gq-G11/genetics; Humans; Intracellular Signaling Peptides and Proteins/metabolism; Muscle Proteins/metabolism; NFATC Transcription Factors/metabolism; Signal Transduction/drug effects; Vascular Malformations/genetics; Journal Article |
| Description: |
Capillary malformations (CMs) are congenital vascular lesions caused by somatic mutations in the GNAQ gene, most frequently resulting in a p.R183Q substitution in the Gαq protein in endothelial cells. However, the downstream signaling pathways by which Gαq-R183Q impairs vascular function remain poorly defined. To address this, we generated human dermal endothelial cells lacking endogenous Gαq and expressing the Gαq-R183Q mutant. Next, using SILAC-based quantitative proteomics, we mapped the Gαq-R183Q-induced endothelial phosphoproteome. These analyses identified aberrant activation of the Calcineurin-NFAT-DSCR1.4 signaling cascade as a key pathogenic feature. NFAT dysregulation and DSCR1 expression in endothelial cells were confirmed in patient-derived biopsies. Pharmacological inhibition of Calcineurin with tacrolimus partially normalized NFAT signaling in Gαq-R183Q endothelial cells. Strikingly, genetic depletion of DSCR1 in Gαq-R183Q cells fully restored Calcineurin/NFAT signaling and enabled proper endothelial migration and angiogenic sprouting, highlighting DSCR1 as a critical effector of Gαq-R183Q signaling in CMs. These findings reveal a druggable signaling circuit downstream of Gαq-R183Q that may serve as a foundation for future therapies targeting GNAQ-driven vascular malformations, including Sturge-Weber syndrome. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0969-6970 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/469393 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/469393 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.818C82E2 |
| Database: |
BASE |