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Nuclear signalling by tumour-associated antigen EpCAM

Nature Cell Biology volume 11, pages 162–171 (2009)Cite this article

Abstract

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, β-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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Figure 1: Proteolytic cleavage of EpCAM in cancer cells.
Figure 2: Effect of specific protease inhibitors on EpCAM cleavage and signalling.
Figure 3: Effect of TACE and presenilin-specific siRNAs on EpCAM signalling.
Figure 4: A large nuclear complex containing EpICD.
Figure 5: EpEX as soluble ligand and inducer of EpCAM signalling.
Figure 6: EpICD is oncogenic in vivo.
Figure 7: Model of the EpCAM signalling pathway.

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Acknowledgements

Work was supported by funding from the Deutsche Krebshilfe, Mildred-Scheel-Stiftung to M.M. and O.G. We are indebted to Jürgen Haas for technical help. We thank Wenlong Bai for FHL-2–GST constructs. We thank Ralf Schulz for support with in vivo fluorescence imaging. Animal experiments were conducted at the Walter Brendel Center (Director, U. Pohl).

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Author notes

  1. Markus Munz and Olivier Gires: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical 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

    Dorothea Maetzel, Sabine Denzel, Michael Benk, Markus Munz & Olivier Gires

  2. Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, Munich, 81377, Germany

    Brigitte Mack, Martin Canis, Cuong Kieu & Olivier Gires

  3. Institute of Pathology, University of Zurich, Birmensdorferstr. 497, Zurich, 8063, Switzerland

    Philip Went

  4. Helmholtz-Zentrum München, German Research Center for Environmental Health, Marchioninistr. 15, Munich, 81377, Germany

    Peer Papior

  5. Micromet, Inc., 6707 Democracy Blvd., Bethesda, 20817, MD, USA

    Patrick A. Baeuerle & Markus Munz

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Contributions

D.M. and M.M. planned the project, performed experiments and analysed the data; S.D., B.M., M.C., M.B., C.K. and P.P. performed experiments; P.W. provided material support; O.G. planned the project; P.A.B. and O.G. analysed the data and wrote the manuscript.

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Correspondence to Olivier Gires.

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Competing interests

Markus Munz and Patrick A. Baeuerle are employees of Micromet Inc., Bethesda, Md, USA.

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Maetzel, D., Denzel, S., Mack, B. et al. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11, 162–171 (2009). https://doi.org/10.1038/ncb1824

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