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Characterization of the cell membrane-associated products of the Neuregulin 4 gene

Oncogene volume 27, pages 715–720 (2008)Cite this article

Abstract

The NRG4 gene is a member of a family of four genes that encode a class of epidermal growth factors. This gene has been reported to express a protein designated here as NRG4A1. We describe here a novel splice variant of the NRG4 gene, NRG4A2, which encodes a C-terminal region containing a predicted type I PDZ-binding peptide. Both NRG4A1 and NRG4A2 were shown to be expressed on the cell surface, as expected by the presence of a predicted transmembrane sequence, and were modified at a single N-linked glycosylation site in the extracellular domain. Significant stabilization of expression of both proteins was seen in the presence of the proteosome inhibitor MG-132 suggesting that they are normally degraded by this system. N-terminal cleavage was inhibited in both isotypes by the broad-spectrum matrix metalloproteinase inhibitor, galardin (GM 6001). A glycosylated, secreted form of NRG4A1 was detected in the cell medium which showed biological activity in two assays, phosphorylation of the HER4 receptor and stimulation of neurite formation in PC-12 cells stably expressing HER4. Transfection and expression of green fluorescent protein-tagged proteins and immunofluorescent staining with specific anti-peptide antibodies showed that NRG4A1 is localized to membrane ruffles, while NRG4A2 has a more punctate membrane distribution.

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Acknowledgements

We are grateful to Dr Richard Williamson (Department of Biosciences, University of Kent, Canterbury, Kent, UK) for help with the molecular modelling. NH is supported by Association of International Cancer Research (AICR), Grant no. 20816.

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Authors and Affiliations

  1. Cancer Biology Laboratory, Research School of Biosciences, University of Kent, Canterbury, UK

    N V L Hayes, R J Newsam & W J Gullick

  2. Centre for Biomedical Informatics, University of Kent, Canterbury, UK

    A J Baines

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  1. N V L Hayes
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  2. R J Newsam
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  3. A J Baines
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  4. W J Gullick
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Correspondence to W J Gullick.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Hayes, N., Newsam, R., Baines, A. et al. Characterization of the cell membrane-associated products of the Neuregulin 4 gene. Oncogene 27, 715–720 (2008). https://doi.org/10.1038/sj.onc.1210689

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