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. 1997 Jul;17(7):4007–4014. doi: 10.1128/mcb.17.7.4007

Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus.

S J Busfield 1, D A Michnick 1, T W Chickering 1, T L Revett 1, J Ma 1, E A Woolf 1, C A Comrack 1, B J Dussault 1, J Woolf 1, A D Goodearl 1, D P Gearing 1
PMCID: PMC232253  PMID: 9199335

Abstract

Members of the epidermal growth factor family of receptors have long been implicated in the pathogenesis of various tumors, and more recently, apparent roles in the developing heart and nervous system have been described. Numerous ligands that activate these receptors have been isolated. We report here on the cloning and initial characterization of a second ligand for the erbB family of receptors. This factor, which we have termed Don-1 (divergent of neuregulin 1), has structural similarity with the neuregulins. We have isolated four splice variants, two each from human and mouse, and have shown that they are capable of inducing tyrosine phosphorylation of erbB3, erbB4, and erbB2. In contrast to those of neuregulin, high levels of expression of Don-1 are restricted to the cerebellum and dentate gyrus in the adult brain and to fetal tissues.

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Selected References

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  1. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  2. Bacus S. S., Zelnick C. R., Plowman G., Yarden Y. Expression of the erbB-2 family of growth factor receptors and their ligands in breast cancers. Implication for tumor biology and clinical behavior. Am J Clin Pathol. 1994 Oct;102(4 Suppl 1):S13–S24. [PubMed] [Google Scholar]
  3. Barbacci E. G., Guarino B. C., Stroh J. G., Singleton D. H., Rosnack K. J., Moyer J. D., Andrews G. C. The structural basis for the specificity of epidermal growth factor and heregulin binding. J Biol Chem. 1995 Apr 21;270(16):9585–9589. doi: 10.1074/jbc.270.16.9585. [DOI] [PubMed] [Google Scholar]
  4. Burt A. M. Morphologic abnormalities in the postnatal differentiation of CA1 pyramidal cells and granule cells in the hippocampal formation of the ataxic mouse. Anat Rec. 1980 Jan;196(1):61–69. doi: 10.1002/ar.1091960107. [DOI] [PubMed] [Google Scholar]
  5. Carraway K. L., 3rd, Cantley L. C. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell. 1994 Jul 15;78(1):5–8. doi: 10.1016/0092-8674(94)90564-9. [DOI] [PubMed] [Google Scholar]
  6. Chen M. S., Bermingham-McDonogh O., Danehy F. T., Jr, Nolan C., Scherer S. S., Lucas J., Gwynne D., Marchionni M. A. Expression of multiple neuregulin transcripts in postnatal rat brains. J Comp Neurol. 1994 Nov 15;349(3):389–400. doi: 10.1002/cne.903490306. [DOI] [PubMed] [Google Scholar]
  7. Corfas G., Rosen K. M., Aratake H., Krauss R., Fischbach G. D. Differential expression of ARIA isoforms in the rat brain. Neuron. 1995 Jan;14(1):103–115. doi: 10.1016/0896-6273(95)90244-9. [DOI] [PubMed] [Google Scholar]
  8. Danilenko D. M., Ring B. D., Lu J. Z., Tarpley J. E., Chang D., Liu N., Wen D., Pierce G. F. Neu differentiation factor upregulates epidermal migration and integrin expression in excisional wounds. J Clin Invest. 1995 Feb;95(2):842–851. doi: 10.1172/JCI117734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dong Z., Brennan A., Liu N., Yarden Y., Lefkowitz G., Mirsky R., Jessen K. R. Neu differentiation factor is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron. 1995 Sep;15(3):585–596. doi: 10.1016/0896-6273(95)90147-7. [DOI] [PubMed] [Google Scholar]
  10. 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. 1993 Mar 12;72(5):801–815. doi: 10.1016/0092-8674(93)90407-h. [DOI] [PubMed] [Google Scholar]
  11. Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R., Lemke G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature. 1995 Nov 23;378(6555):390–394. doi: 10.1038/378390a0. [DOI] [PubMed] [Google Scholar]
  12. Goodearl A. D., 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. 1995 Sep;130(6):1423–1434. doi: 10.1083/jcb.130.6.1423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ho A. S., Liu Y., Khan T. A., Hsu D. H., Bazan J. F., Moore K. W. A receptor for interleukin 10 is related to interferon receptors. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11267–11271. doi: 10.1073/pnas.90.23.11267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  15. Karunagaran D., Tzahar E., Beerli R. R., Chen X., Graus-Porta D., Ratzkin B. J., Seger R., Hynes N. E., Yarden Y. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J. 1996 Jan 15;15(2):254–264. [PMC free article] [PubMed] [Google Scholar]
  16. Kramer R., Bucay N., Kane D. J., Martin L. E., Tarpley J. E., Theill L. E. Neuregulins with an Ig-like domain are essential for mouse myocardial and neuronal development. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4833–4838. doi: 10.1073/pnas.93.10.4833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lee K. F., Simon H., Chen H., Bates B., Hung M. C., Hauser C. Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature. 1995 Nov 23;378(6555):394–398. doi: 10.1038/378394a0. [DOI] [PubMed] [Google Scholar]
  18. Marchionni M. A., Goodearl A. D., Chen M. S., Bermingham-McDonogh O., Kirk C., Hendricks M., Danehy F., Misumi D., Sudhalter J., Kobayashi K. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993 Mar 25;362(6418):312–318. doi: 10.1038/362312a0. [DOI] [PubMed] [Google Scholar]
  19. Marikovsky M., Lavi S., Pinkas-Kramarski R., Karunagaran D., Liu N., Wen D., Yarden Y. ErbB-3 mediates differential mitogenic effects of NDF/heregulin isoforms on mouse keratinocytes. Oncogene. 1995 Apr 6;10(7):1403–1411. [PubMed] [Google Scholar]
  20. Meyer D., Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995 Nov 23;378(6555):386–390. doi: 10.1038/378386a0. [DOI] [PubMed] [Google Scholar]
  21. 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 U S A. 1995 Feb 28;92(5):1431–1435. doi: 10.1073/pnas.92.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mudge A. W. Neural development: new ligands for Neu? Curr Biol. 1993 Jun 1;3(6):361–364. doi: 10.1016/0960-9822(93)90201-x. [DOI] [PubMed] [Google Scholar]
  23. Orr-Urtreger A., Trakhtenbrot L., Ben-Levy R., Wen D., Rechavi G., Lonai P., Yarden Y. Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1867–1871. doi: 10.1073/pnas.90.5.1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  25. Peles E., Yarden Y. Neu and its ligands: from an oncogene to neural factors. Bioessays. 1993 Dec;15(12):815–824. doi: 10.1002/bies.950151207. [DOI] [PubMed] [Google Scholar]
  26. Plowman G. D., Culouscou J. M., Whitney G. S., Green J. M., Carlton G. W., Foy L., Neubauer M. G., Shoyab M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746–1750. doi: 10.1073/pnas.90.5.1746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Plowman G. D., Green J. M., Culouscou J. M., Carlton G. W., Rothwell V. M., Buckley S. Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature. 1993 Dec 2;366(6454):473–475. doi: 10.1038/366473a0. [DOI] [PubMed] [Google Scholar]
  28. Sliwkowski M. X., Schaefer G., Akita R. W., Lofgren J. A., Fitzpatrick V. D., Nuijens A., Fendly B. M., Cerione R. A., Vandlen R. L., Carraway K. L., 3rd Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem. 1994 May 20;269(20):14661–14665. [PubMed] [Google Scholar]
  29. Tartaglia L. A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., Richards G. J., Campfield L. A., Clark F. T., Deeds J. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995 Dec 29;83(7):1263–1271. doi: 10.1016/0092-8674(95)90151-5. [DOI] [PubMed] [Google Scholar]
  30. Tzahar E., Levkowitz G., Karunagaran D., Yi L., Peles E., Lavi S., Chang D., Liu N., Yayon A., Wen D. ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem. 1994 Oct 7;269(40):25226–25233. [PubMed] [Google Scholar]
  31. Vartanian T., Corfas G., Li Y., Fischbach G. D., Stefansson K. A role for the acetylcholine receptor-inducing protein ARIA in oligodendrocyte development. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11626–11630. doi: 10.1073/pnas.91.24.11626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wallasch C., Weiss F. U., Niederfellner G., Jallal B., Issing W., Ullrich A. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J. 1995 Sep 1;14(17):4267–4275. doi: 10.1002/j.1460-2075.1995.tb00101.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wen D., Peles E., Cupples R., Suggs S. V., Bacus S. S., Luo Y., Trail G., Hu S., Silbiger S. M., Levy R. B. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992 May 1;69(3):559–572. doi: 10.1016/0092-8674(92)90456-m. [DOI] [PubMed] [Google Scholar]

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