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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
dependent gamma-secretase; ep-cam; breast-cancer; beta-catenin; cell-proliferation; adhesion molecule; colorectal-cancer; stem-cells; c-myc; target
ISSN (print) / ISBN
1465-7392
e-ISSN
1476-4679
Zeitschrift
Nature Cell Biology
Quellenangaben
Band: 11,
Heft: 2,
Seiten: 162-171
Verlag
Nature Publishing Group
Begutachtungsstatus
Peer reviewed
Institut(e)
CCG Molecular Oncology (AGV-KON)
Research Unit Gene Vector (AGV)
Research Unit Gene Vector (AGV)