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Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor

Oncogene volume 20, pages 5199–5209 (2001)Cite this article

Abstract

The four members of the EGF receptor family are capable of homomeric as well as heteromeric interactions. HER-2/neu (erbB-2) dominates as the preferred coreceptor that amplifies mitogenic signaling. An alternative HER-2/neu product, herstatin, consists of a segment of the ectodomain of p185HER-2 and an intron-encoded C-terminus. Recombinant herstatin was found to bind with nM affinity and inhibit p185HER-2. To further examine the impact on receptor activity, herstatin was expressed with various receptor tyrosine kinases. In CHO cells that overexpressed HER-2, herstatin caused a sevenfold inhibition of colony formation that corresponded to a reduction in the tyrosine phosphorylation of p185HER-2. Herstatin also prevented HER-2 mediated transactivation of the kinase impaired HER-3 as reflected in transphosphorylation of HER-3 and heteromers between HER-2 and HER-3. In EGF receptor-overexpressing cells, EGF induction of receptor dimerization and tyrosine phosphorylation were reduced more than 90%, and receptor down-regulation as well as colony formation were also suppressed by coexpression with herstatin. Inhibition was selective for the EGF receptor family since herstatin expression did not reduce tyrosine phosphorylation mediated by the FGF receptor-2 or by insulin-like growth factor -1. Herstatin bound to the EGF receptor as well as to p185HER-2 in pull-down assays suggesting that complex formation may be involved in receptor inhibition. Our findings indicate that herstatin has the capability to negatively regulate combinations of interactions between group I receptor tyrosine kinases that confer synergistic growth signals.

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Acknowledgements

We acknowledge Adam Evans and John Adelman for critically reading the manuscript. We thank Mark Greene for providing the T691neu mutant and Tracy Ram for the HER-3 expression plasmid. This study was supported by grants from the National Cancer Institute, NCI.

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Author notes

  1. Nicolas G Azios and Farida Jhabvala Romero: NG Azios and FJ Romero contributed equally to this paper.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Oregon Health Sciences University, Portland, OR 97201, Oregon, USA

    Nicolas G Azios, Farida Jhabvala Romero, Michael C Denton & Gail M Clinton

  2. Department of Otolaryngology, University of Southern California, Los Angeles, CA 90033, California, USA

    Joni K Doherty

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  1. Nicolas G Azios
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Correspondence to Gail M Clinton.

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Azios, N., Romero, F., Denton, M. et al. Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor. Oncogene 20, 5199–5209 (2001). https://doi.org/10.1038/sj.onc.1204555

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