PXD067749

PXD067749 is an original dataset announced via ProteomeXchange.

Title	SMAD4-NFATc1 protein-protein interaction informed therapeutic vulnerability in SMAD4-deficient pancreatic cancer
Description	Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a median survival rate of approximately six months. While genetic profiling has uncovered common mutations in PDAC, developing targeted therapeutic strategies remains challenging. SMAD4 is frequently mutated or deleted in 30-55% of PDAC patients and correlates with poor survival rates. Such mutations frequently result in loss-of-function, thereby disrupting normal cell cycle regulation and contributing to tumorigenesis. Therefore, translating SMAD4 genotype into actionable targets are highly desired for therapeutic innovation in PDAC. In this study, we performed a SMAD4-focused oncogenic protein-protein interaction (oncoPPI) network mapping and revealed a direct physical interaction between SMAD4 and NFATc1. We found that SMAD4 interacts with NFATc1 in a TGF-independent and NFATc1 phosphorylation-dependent manner. Further, SMAD4 sequesters NFATc1 in cytoplasm and inhibits NFATc1 transcriptional activity. In PDAC cells, SMAD4-loss releases its inhibitory activity on NFATc1, activates NFATc1 transcriptional activity which drives STAT3 mRNA and protein upregulation. Pharmacological profiling identified multiple STAT3 inhibitors selectively inhibit the growth of SMAD4-loss PDAC cells. These results suggested a rewired SMAD4-NFATc1-STAT3 axis and targeting STAT3 as a potential therapeutic strategy in SMAD4-loss PDAC.
HostingRepository	PRIDE
AnnounceDate	2026-02-02
AnnouncementXML	Submission_2026-02-01_17:32:45.328.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	David Gordon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2025-08-26 09:16:13	ID requested
⏵ 1	2026-02-01 17:32:46	announced

Ouyang W, Hao J, Niu Q, Douglass EF, Beusch CM, Gordon DE, Hall M, Moffitt RA, Du Y, Mo X, -independent SMAD4-NFATc1-STAT3 regulatory axis. J Mol Cell Biol, 17(6):(2026) [pubmed]

10.1093/jmcb/mjaf028;

submitter keyword: SMAD4, pancreatic cancer

Xiulei Mo
contact affiliation	Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
contact email	xiu-lei.mo@emory.edu
lab head
David Gordon
contact affiliation	Emory University
contact email	david.ezra.gordon@emory.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067749
     1. Label: PRIDE project
     2. Name: SMAD4-NFATc1 protein-protein interaction informed therapeutic vulnerability in SMAD4-deficient pancreatic cancer