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Nuclear signalling by tumour-associated antigen EpCAM
Dorothea Maetzel1, Sabine Denzel, Brigitte Mack
1Clinical Cooperation Group Molecular Oncology, Helmholtz-Zentrum München, German Research Center for Environmental Health, and Head and Neck Research Dept,. Ludwig-Maximilians-University of Munich, Germany.
Nature Cell Biology
|January 13, 2009
Summary
Regulated intramembrane proteolysis activates EpCAM, a protein overexpressed in cancer, as a mitogenic signal. Its intracellular domain (EpICD) translocates to the nucleus, driving cancer cell proliferation and gene transcription.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Epithelial cell adhesion molecule (EpCAM) is overexpressed in various carcinomas and cancer-initiating cells.
- The precise role of EpCAM in cancer proliferation beyond cell adhesion is not well understood.
Purpose of the Study:
- To elucidate the mechanism by which EpCAM contributes to cell proliferation and cancer.
- To investigate the role of regulated intramembrane proteolysis in EpCAM signaling.
Main Methods:
- Investigated EpCAM cleavage by TACE and presenilin-2 in vitro and in vivo.
- Analyzed nuclear translocation of EpCAM's intracellular domain (EpICD).
- Assessed the oncogenic potential of EpICD in immunodeficient mice and its presence in human colon carcinoma nuclei.
Main Results:
- Regulated intramembrane proteolysis activates EpCAM as a mitogenic signal.
- EpCAM cleavage releases EpICD, which translocates to the nucleus.
- EpICD forms a complex with FHL2, beta-catenin, and Lef-1, inducing gene transcription and promoting tumor growth.
- Nuclear EpICD is detected in colon carcinoma but not normal tissue.
Conclusions:
- EpCAM functions as a mitogenic signal transducer through regulated intramembrane proteolysis and nuclear signaling.
- Nuclear EpICD is oncogenic and plays a significant role in colon carcinoma proliferation.
- This mechanism explains EpCAM's contribution to cancer cell proliferation.
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