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000140001 0247_ $$2doi$$a10.1074/jbc.RA118.002776
000140001 0247_ $$2pmid$$apmid:29700109
000140001 0247_ $$2pmc$$apmc:PMC5995519
000140001 0247_ $$2ISSN$$a0021-9258
000140001 0247_ $$2ISSN$$a1067-8816
000140001 0247_ $$2ISSN$$a1083-351X
000140001 0247_ $$2altmetric$$aaltmetric:39598280
000140001 037__ $$aDZNE-2020-06323
000140001 041__ $$aEnglish
000140001 082__ $$a540
000140001 1001_ $$aTretter, Jana Ylva$$b0
000140001 245__ $$aA high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor.
000140001 260__ $$aBethesda, Md.$$bSoc.60645$$c2018
000140001 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2018-04-26
000140001 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2018-06-08
000140001 3367_ $$2DRIVER$$aarticle
000140001 3367_ $$2DataCite$$aOutput Types/Journal article
000140001 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1588085759_27570
000140001 3367_ $$2BibTeX$$aARTICLE
000140001 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000140001 3367_ $$00$$2EndNote$$aJournal Article
000140001 520__ $$aEpithelial cell-adhesion molecule (EpCAM) is a transmembrane protein that regulates cell cycle progression and differentiation and is overexpressed in many carcinomas. The EpCAM-induced mitogenic cascade is activated via regulated intramembrane proteolysis (RIP) of EpCAM by ADAM and γ-secretases, generating the signaling-active intracellular domain EpICD. Because of its expression pattern and molecular function, EpCAM is a valuable target in prognostic and therapeutic approaches for various carcinomas. So far, several immunotherapeutic strategies have targeted the extracellular domain of EpCAM. However, targeting the intracellular signaling cascade of EpCAM holds promise for specifically interfering with EpCAM's proliferation-stimulating signaling cascade. Here, using a yellow fluorescence protein-tagged version of the C-terminal fragment of EpCAM, we established a high-content screening (HCS) of a small-molecule compound library (n = 27,280) and characterized validated hits that target EpCAM signaling. In total, 128 potential inhibitors were initially identified, of which one compound with robust inhibitory effects on RIP of EpCAM was analyzed in greater detail. In summary, our study demonstrates that the development of an HCS for small-molecule inhibitors of the EpCAM signaling pathway is feasible. We propose that this approach may also be useful for identifying chemical compounds targeting other disorders involving membrane cleavage-dependent signaling pathways.
000140001 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000140001 588__ $$aDataset connected to CrossRef, PubMed,
000140001 650_7 $$2NLM Chemicals$$aEpithelial Cell Adhesion Molecule
000140001 650_7 $$2NLM Chemicals$$aSmall Molecule Libraries
000140001 650_2 $$2MeSH$$aCell Proliferation: drug effects
000140001 650_2 $$2MeSH$$aDrug Evaluation, Preclinical: methods
000140001 650_2 $$2MeSH$$aEpithelial Cell Adhesion Molecule: antagonists & inhibitors
000140001 650_2 $$2MeSH$$aEpithelial Cell Adhesion Molecule: metabolism
000140001 650_2 $$2MeSH$$aHEK293 Cells
000140001 650_2 $$2MeSH$$aHigh-Throughput Screening Assays: methods
000140001 650_2 $$2MeSH$$aHumans
000140001 650_2 $$2MeSH$$aSignal Transduction: drug effects
000140001 650_2 $$2MeSH$$aSmall Molecule Libraries: chemistry
000140001 650_2 $$2MeSH$$aSmall Molecule Libraries: pharmacology
000140001 650_2 $$2MeSH$$aTranscription, Genetic: drug effects
000140001 7001_ $$aSchorpp, Kenji$$b1
000140001 7001_ $$aLuxenburger, Elke$$b2
000140001 7001_ $$aTrambauer, Johannes$$b3
000140001 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b4$$udzne
000140001 7001_ $$aHadian, Kamyar$$b5
000140001 7001_ $$0P:(DE-HGF)0$$aGires, Olivier$$b6$$eCorresponding author
000140001 7001_ $$aNiessing, Dierk$$b7
000140001 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.ra118.002776$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2018-04-26$$n23$$p8994-9005$$tJournal of Biological Chemistry$$v293$$x0021-9258$$y2018
000140001 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.RA118.002776$$gVol. 293, no. 23, p. 8994 - 9005$$n23$$p8994-9005$$q293:23<8994 - 9005$$tThe journal of biological chemistry$$v293$$x0021-9258$$y2018
000140001 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995519
000140001 909CO $$ooai:pub.dzne.de:140001$$pVDB
000140001 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2000023$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b4$$kDZNE
000140001 9131_ $$0G:(DE-HGF)POF3-342$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$aDE-HGF$$bForschungsbereich Gesundheit$$lErkrankungen des Nervensystems$$vDisease Mechanisms and Model Systems$$x0
000140001 9141_ $$y2018
000140001 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bJ BIOL CHEM : 2019$$d2021-05-04
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000140001 9201_ $$0I:(DE-2719)1110000-1$$kAG Steiner$$lBiochemistry of γ-Secretase$$x0
000140001 980__ $$ajournal
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