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000165254 1001_ $$0P:(DE-2719)2812025$$aGüner, Gökhan$$b0$$eFirst author
000165254 245__ $$aProteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.
000165254 260__ $$aHeidelberg$$bEMBO Press$$c2022
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000165254 520__ $$aFn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ-secretase in tumor cells reduced sFn14 secretion, increased full-length Fn14 at the cell surface, and enhanced TWEAK ligand-stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ-Secretase-dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ-secretase inhibitor prior to chimeric antigen receptor (CAR)-T-cell treatment. Taken together, our study demonstrates a novel function for γ-secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ-secretase activity in vivo.
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000165254 650_7 $$2Other$$aAlzheimer's disease
000165254 650_7 $$2Other$$aTNR12
000165254 650_7 $$2Other$$aectodomain shedding
000165254 650_7 $$2Other$$aglioblastoma
000165254 650_7 $$2Other$$aintramembrane proteolysis
000165254 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases
000165254 650_2 $$2MeSH$$aAnimals
000165254 650_2 $$2MeSH$$aBiomarkers
000165254 650_2 $$2MeSH$$aCytokine TWEAK
000165254 650_2 $$2MeSH$$aHumans
000165254 650_2 $$2MeSH$$aLigands
000165254 650_2 $$2MeSH$$aMice
000165254 650_2 $$2MeSH$$aReceptors, Cell Surface: metabolism
000165254 650_2 $$2MeSH$$aReceptors, Chimeric Antigen
000165254 650_2 $$2MeSH$$aReceptors, Tumor Necrosis Factor: metabolism
000165254 650_2 $$2MeSH$$aTWEAK Receptor
000165254 650_2 $$2MeSH$$aTumor Necrosis Factor-alpha
000165254 7001_ $$0P:(DE-2719)9001720$$aAssfalg, Marlene$$b1
000165254 7001_ $$aZhao, Kai$$b2
000165254 7001_ $$aDreyer, Tobias$$b3
000165254 7001_ $$aLahiri, Shibojyoti$$b4
000165254 7001_ $$aLo, Yun$$b5
000165254 7001_ $$0P:(DE-2719)9002486$$aSlivinschi, Bianca$$b6$$udzne
000165254 7001_ $$00000-0003-2993-8249$$aImhof, Axel$$b7
000165254 7001_ $$0P:(DE-2719)2813355$$aJocher, Georg$$b8
000165254 7001_ $$0P:(DE-2719)2812236$$aStrohm, Laura$$b9
000165254 7001_ $$00000-0002-9184-7607$$aBehrends, Christian$$b10
000165254 7001_ $$0P:(DE-2719)9001125$$aLangosch, Dieter$$b11
000165254 7001_ $$00000-0002-3706-6738$$aBronger, Holger$$b12
000165254 7001_ $$00000-0002-8216-9410$$aNimsky, Christopher$$b13
000165254 7001_ $$00000-0002-2773-3357$$aBartsch, Jörg W$$b14
000165254 7001_ $$aRiddell, Stanley R$$b15
000165254 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b16
000165254 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan$$b17$$eLast author
000165254 773__ $$0PERI:(DE-600)2485479-7$$a10.15252/emmm.202216084$$gVol. 14, no. 10$$n10$$pe16084$$tEMBO molecular medicine$$v14$$x1715-4684$$y2022
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