Nuclear signalling by tumour-associated antigen EpCAM

Maetzel, Dorothea and Denzel, Sabine and Mack, Brigitte and Canis, Martin and Went, Philip and Benk, Michael and Kieu, Cuong and Papior, Peer and Baeuerle, Patrick A. and Munz, Markus and Gires, Olivier. (2009) Nuclear signalling by tumour-associated antigen EpCAM. Nature cell biology, Vol. 11. pp. 162-171.

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Official URL: http://edoc.unibas.ch/dok/A6005230

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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.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
UniBasel Contributors:Went, Philip Th.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Mar 2013 11:14
Deposited On:01 Mar 2013 11:12

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