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Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

Oncogene volume 18, pages 2681–2689 (1999)Cite this article

Abstract

The ErbB/HER family of receptor tyrosine kinases consists of four receptors that bind a large number of growth factor ligands sharing an epidermal growth factor- (EGF)-like motif. Whereas ErbB-1 binds seven different ligands whose prototype is EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain. A synthetic peptide encompassing the full-length EGF-like domain can induce growth of interleukin-dependent cells ectopically expressing ErbB-4, but not cells expressing the other three ErbB proteins or their combinations. Consistent with specificity to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor. Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA. The primary structure and the pattern of expression of NRG-4, together with the strict specificity of this growth factor to ErbB-4, suggest a physiological role distinct from that of the known ErbB ligands.

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Acknowledgements

We thank Roni Seger for anti-MAPK antibodies, Carmen Birchmeier for helpful advice, Irit Orr, Chaya Kalcheim and Nitza Kahane for support. D Harari is the recipient of a postdoctoral fellowship from the Israeli Ministry of Science. This work was supported by grants from the US Department of the Army (grant DAMD 17-97-17290), the Israel Academy of Sciences and Humanities (administered by The Israel Science Foundation) and the German Israeli Foundation for Scientific Research and Development.

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Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel

    D Harari, E Tzahar, J Romano, M Shelly & Y Yarden

  2. The National Cancer Institute, Bethesda, 20892, Maryland, USA

    JH Pierce

  3. Pfizer Central Research, Groton, 06340, Connecticut, USA

    GC Andrews

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Harari, D., Tzahar, E., Romano, J. et al. Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 18, 2681–2689 (1999). https://doi.org/10.1038/sj.onc.1202631

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