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The molecular function of transmembrane proline\u2010rich Gla proteins (PRRGs) remains unexplored.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Analysis of pancreatic ductal adenocarcinoma (PDAC) datasets, including transcription profiles, clinical data, and tissue microarrays, was conducted to evaluate PRRG1 expression and its clinical relevance. PDAC cell lines with overexpressed, knockdown, and mutated PRRG1 were developed to study biological functions and pathways using RNA\u2010seq, co\u2010immunoprecipitation with mass spectrometry, Western blotting, and immunofluorescence. In vivo xenograft and orthotopic models assessed PRRG1's impact on PDAC progression, with and without warfarin treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PRRG1 was significantly upregulated in PDAC compared to normal pancreas, correlating with poorer patient survival. PRRG1 knockdown reduced PDAC cell proliferation, anchorage\u2010independent growth in vitro, and tumor growth in vivo. PRRG1 localized at the plasma membrane, interacted with the HECT E3 ligase NEDD4 via the C\u2010terminal PPXY motif, and promoted NEDD4 self\u2010ubiquitination, reducing its protein levels. PRRG1 knockdown elevated NEDD4, destabilizing the oncoprotein KRAS and receptor EGFR, and attenuating downstream signaling and macropinocytosis under nutrient deprivation. The vitamin K\u2010dependent Gla modification of PRRG1 was crucial for its membrane localization and pro\u2010tumorigenic effects, and was inhibited by low\u2010dose warfarin, a clinical vitamin K antagonist.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This study identifies PRRG1 as a key regulator of pro\u2010tumorigenic signaling in PDAC, suggesting the potential of repurposing the anticoagulant warfarin as a therapeutic strategy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>PRRG1 is identified as the transmembrane Gla protein mediating PDAC malignancy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PRRG1 recruits and induces self\u2010ubiquitination of membrane\u2010anchoring E3 ligase NEDD4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PRRG1 exerts a protective role toward KRAS and EGFR by inhibiting NEDD4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The anticoagulant warfarin can be utilized to inhibit PRRG1 and PDAC advancement.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70191","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T22:30:33Z","timestamp":1737585033000},"source":"Crossref","is-referenced-by-count":6,"title":["Vitamin K\u2010dependent gamma\u2010carboxyglutamic acid protein 1 promotes pancreatic ductal adenocarcinoma progression through stabilizing oncoprotein KRAS and tyrosine kinase receptor EGFR"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6817-9631","authenticated-orcid":false,"given":"Zheng","family":"Wu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Systems Medicine for Cancer Shanghai Cancer Institute Ren Ji Hospital School of Medicine Shanghai Jiao Tong University  Shanghai P.R. 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