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Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases

Abstract

The neuregulins (NRGs) are a family of multipotent epidermal-growth-factor-like (EGF-like) factors that arise from splice variants of a single gene. They influence the growth, differentiation, survival and fate of several cell types. We have now discovered a set of new neuregulin-like growth factors, which we call neuregulin-2 (NRG-2): these are encoded by their own gene and exhibit a distinct expression pattern in adult brain and developing heart. Like NRG-1, the EGF-like domain of the new ligands binds to both the ErbB3- and ErbB4-receptor tyrosine kinases. However, NRG-2 stimulates different ErbB-receptor tyrosine-phosphorylation profiles from NRG-1. Our results indicate that NRG-1 and NRG-2 mediate distinct biological processes by acting at different sites in tissues and eliciting different biochemical responses in cells.

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References

  1. Goodearl, A. D. J., Yee, A. G., Sandrock, A. W. Jr, Corfas, G. & Fischbach, G. D. ARIA is concentrated in the synaptic basal lamina of the developing chick neuromuscular junction. J. Cell Biol. 130, 1423–1434 (1995).

    Article  CAS  Google Scholar 

  2. Jo, S. A., Zhu, X., Marchionni, M. A. & Burden, S. J. Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature 373, 158–161 (1995).

    Article  ADS  CAS  Google Scholar 

  3. Carraway, K. L. & Burden, S. J. Neuregulins and their receptors. Curr. Opin. Neurobiol. 5, 606–612 (1995).

    Article  CAS  Google Scholar 

  4. Lemke, G. Neuregulins in development. Mol. Cell. Neurosci. 7, 247–262 (1996).

    Article  CAS  Google Scholar 

  5. Morrissey, T. K., Levi, A. D., Nuijens, A., Sliwkowski, M. X. & Bunge, R. P. Axon-induced mitogenesis of human Schwann cells involves heregulin and p185erbB2. Proc. Natl Acad. Sci. USA 92, 1431–1435 (1995).

    Article  ADS  CAS  Google Scholar 

  6. Dong, Z. et al. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat schwann cell precursors. Neuron 15, 585–596 (1995).

    Article  CAS  Google Scholar 

  7. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    Article  ADS  CAS  Google Scholar 

  8. Gassmann, M. et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378, 390–394 (1995).

    Article  ADS  CAS  Google Scholar 

  9. Lee, K.-F. et al. Requirement for neurgeulin receptor ErbB2 in neural and cardiac development. Nature 378, 394–398 (1995).

    Article  ADS  CAS  Google Scholar 

  10. Carraway, K. L. Involvement of the neuregulins and their receptors in cardiac and neural development. BioEssays 18, 263–266 (1996).

    Article  CAS  Google Scholar 

  11. Stern, D. F. & Hynes, N. E. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim. Biophys. Acta 1198, 165–184 (1994).

    PubMed  Google Scholar 

  12. Marchionni, M. A. et al. Glial growth factors are alternatively spliced ErbB2 ligands expressed in the nervous system. Nature 362, 312–318 (1993).

    Article  ADS  CAS  Google Scholar 

  13. Falls, D. L., Rosen, K. M., Corfas, G., Lane, W. S. & Fischbach, G. D. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the Neu ligand family. Cell 72, 801–815 (1993).

    Article  CAS  Google Scholar 

  14. Holmes, W. E. et al. Identification of heregulin, a specific activator of p185erbB2. Science 256, 1205–1210 (1992).

    Article  ADS  CAS  Google Scholar 

  15. Wen, D. et al. Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell 69, 559–572 (1992).

    Article  CAS  Google Scholar 

  16. Carraway, K. L. et al. The erbB3 gene product is a receptor for heregulin. J. Biol. Chem. 269, 14303–14306 (1994).

    CAS  PubMed  Google Scholar 

  17. Plowman, G. D. et al. Heregulin induces tyrosine phosphorylation of HER4/pl80erbB4. Nature 366, 473–475 (1993).

    Article  ADS  CAS  Google Scholar 

  18. Tzahar, E. et al. ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all neu differentiation factor/heregulin isoforms. J. Biol. Chem. 269, 25226–25233 (1994).

    CAS  PubMed  Google Scholar 

  19. Carraway, K. L. & Cantley, L. C. A neu acquaintance for ErbB3 and ErbB4: A role for receptor heterodimerization in growth signaling. Cell 78, 5–8 (1994).

    Article  CAS  Google Scholar 

  20. Alimandi, M. et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 10, 1813–1821 (1995).

    CAS  PubMed  Google Scholar 

  21. Pinkas-Kramarski, R. et al. Diversification of neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 15, 2452–2467 (1995).

    Article  Google Scholar 

  22. Riese, D. J., van Raaij, T. M., Plowman, G. D., Andrews, G. C. & Stern, D. F. The cellular response to neuregulins is governed by complex interactions of the erbB receptor family. Mol. Cell. Biol. 15, 5770–5776 (1995).

    Article  CAS  Google Scholar 

  23. Chen, M. S. et al. Expression of multiple neuregulin transcripts in postnatal rat brains. J. Comp. Neurol. 349, 389–400 (1994).

    Article  CAS  Google Scholar 

  24. Corfas, G., Rosen, K. M., Aratake, H., Krauss, R. & Fischbach, G. D. Differential expression of ARIA isoforms in the rat brain. Neuron 14, 103–115 (1995).

    Article  CAS  Google Scholar 

  25. Culouscou, J. M., Plowman, G. D., Carlton, G. W., Green, J. M. & Shoyab, M. Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. J. Biol. Chem. 268, 18407–18410 (1993).

    CAS  PubMed  Google Scholar 

  26. Graus-Porta, D., Beerli, R. R. & Hynes, N. E. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs neu differentiation factor and epidermal growth factor signaling. Mol. Cell. Biol. 15, 1182–1191 (1995).

    Article  CAS  Google Scholar 

  27. Karunagaran, D. et al. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 15, 254–264 (1996).

    Article  CAS  Google Scholar 

  28. Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 (1993).

    Article  CAS  Google Scholar 

  29. Lai, C. & Lemke, G. An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system. Neuron 6, 691–704 (1991).

    Article  CAS  Google Scholar 

  30. Guy, P. M., Platko, J. V., Cantley, L. C., Cerione, R. A. & Carraway, K. L. III Insect cell-expressed p180erbB3 posesesses an impaired tyrosine kinase activity. Proc. Natl Acad. Sci. USA 91, 8132–8136 (1994).

    Article  ADS  CAS  Google Scholar 

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Carraway III, K., Weber, J., Unger, M. et al. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 387, 512–516 (1997). https://doi.org/10.1038/387512a0

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