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Open Access Green as soon as Postprint is submitted to ZB.
Nuclear signalling by tumour-associated antigen EpCAM.
Nat. Cell Biol. 11, 162-171 (2009)
EpCAM was found to be overexpressed on epithelial progenitors, carcinomas and cancer-initiating cells. The role of EpCAM in proliferation, and its association with cancer is poorly explained by proposed cell adhesion functions. Here we show that regulated intramembrane proteolysis activates EpCAM as a mitogenic signal transducer in vitro and in vivo. This involves shedding of its ectodomain EpEX and nuclear translocation of its intracellular domain EpICD. Cleavage of EpCAM is sequentially catalysed by TACE and presenilin-2. Pharmacological inhibition or genetic silencing of either protease impairs growth-promoting signalling by EpCAM, which is compensated for by EpICD. Released EpICD associates with FHL2, beta-catenin and Lef-1 to form a nuclear complex that contacts DNA at Lef-1 consensus sites, induces gene transcription and is oncogenic in immunodeficient mice. In patients, EpICD was found in nuclei of colon carcinoma but not of normal tissue. Nuclear signalling of EpCAM explains how EpCAM functions in cell proliferation.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
dependent gamma-secretase; ep-cam; breast-cancer; beta-catenin; cell-proliferation; adhesion molecule; colorectal-cancer; stem-cells; c-myc; target
Language
Publication Year
2009
HGF-reported in Year
2009
ISSN (print) / ISBN
1465-7392
e-ISSN
1476-4679
Journal
Nature Cell Biology
Quellenangaben
Volume: 11,
Issue: 2,
Pages: 162-171
Publisher
Nature Publishing Group
Reviewing status
Peer reviewed
Institute(s)
CCG Molecular Oncology (AGV-KON)
Research Unit Gene Vector (AGV)
Research Unit Gene Vector (AGV)
POF-Topic(s)
30203 - Molecular Targets and Therapies
30203 - Molecular Targets and Therapies
Research field(s)
Immune Response and Infection
Immune Response and Infection
PSP Element(s)
G-520700-001
G-501500-001
G-501500-001
DOI
10.1038/ncb1824
Scopus ID
59749103834
PubMed ID
19136966
Erfassungsdatum
2009-07-09