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Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a

Oncogene volume 35, pages 6416–6428 (2016)Cite this article

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Abstract

The Wnt pathway has essential roles in cell proliferation, cell fate determination and tumorigenesis by regulating the expression of a wide range of target genes. As a core signaling cascade, the canonical Wnt pathway is regulated at different levels by numerous proteins. We have previously shown that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and the Wnt3a ligand are co-secreted from cells. We show that although the C'-terminal Lys residue of Wnt3a is critical for its activity and is important for the effect of CPE on the Wnt pathway, CPE does not execute its effect by removing this Wnt3a residue. Interestingly, CPE through its N'-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. Together, our current results provide a mechanistic insight into the way CPE regulates the canonical Wnt signaling pathway.

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Acknowledgements

This work was supported by Rising Tide Foundation for Clinical Cancer Research, by the Gateway for Cancer Research Foundation and by the Israel Science Foundation (Grant no. 20120016).

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Author notes

  1. N Skalka and M Caspi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    N Skalka, M Caspi, L Lahav-Ariel & R Rosin-Arbesfeld

  2. Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA

    Y P Loh

  3. Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    K Hirschberg

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  1. N Skalka
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Correspondence to R Rosin-Arbesfeld.

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Skalka, N., Caspi, M., Lahav-Ariel, L. et al. Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a. Oncogene 35, 6416–6428 (2016). https://doi.org/10.1038/onc.2016.173

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