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A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities

Oncogene volume 26, pages 462–466 (2007)Cite this article

Abstract

In the normal breast, ERBB4 regulates epithelial differentiation and functions as a nuclear chaperone for signal transducer and activator of transcription (STAT) 5A, thereby stimulating milk-gene expression. In addition, ERBB4 functions as a proapoptotic protein, suppressing the growth of malignant cells. We hypothesize that these ERBB4 activities can be marshaled to suppress the growth of breast tumors. To this end, we have created an ERBB4 allele harboring an activating transmembrane mutation (ERBB4-CA) by substituting isoleucine 658 for glutamic acid. This base substitution forms a valine-glutamic acid-glycine activation domain first identified in oncogenic ERBB2/HER2/Neu. Ectopic expression of ERBB4-CA in HEK293T cells resulted in a fivefold increase in receptor tyrosine phosphorylation. Functionally, ERBB4-CA exhibited higher levels of nuclear translocation than wild-type ERBB4, leading to significantly enhanced ERBB4-induced STAT5A simulation of the β-casein promoter. Activated ERBB4 has been demonstrated to induce cell killing of breast tumor cells. Significantly, ERBB4-CA potentiated the proapoptotic function of ERBB4 in each breast, prostate and ovarian cancer cell line tested. Untransformed cell lines were resistant to both ERBB4 and ERBB4-CA-mediated apoptosis underscoring the potential utility of active ERBB4 signaling for the therapeutic intervention of human cancer.

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Acknowledgements

We thank Amy Notwick for editing this manuscript and members of the Jones laboratory for helpful suggestions and critical insight. This work was supported by National Cancer Institute/National Institutes of Health grants RO1CA95783 and RO1CA96717 (FEJ), US Army Medical Research and Material Command grant DAMD17-03-1-0395 (GAV) and funds generously supplied through the National Cancer Coalition and the Tulane Cancer Center.

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Authors and Affiliations

  1. Department of Structural and Cellular Biology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, USA

    G A Vidal

  2. Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA, USA

    D E Clark & F E Jones

  3. Louisiana State University Health Sciences Center, Gene Therapy Program, The Morphology and Imaging Core Laboratory, New Orleans, LA, USA

    L Marrero

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  1. G A Vidal
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  2. D E Clark
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  3. L Marrero
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  4. F E Jones
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Correspondence to F E Jones.

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Vidal, G., Clark, D., Marrero, L. et al. A constitutively active ERBB4/HER4 allele with enhanced transcriptional coactivation and cell-killing activities. Oncogene 26, 462–466 (2007). https://doi.org/10.1038/sj.onc.1209794

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