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  • Original Paper
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Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation

Oncogene volume 21, pages 8442–8452 (2002)Cite this article

Abstract

During the last decade, several novel members of the Epidermal Growth Factor family of peptide growth factors have been identified. Most prominent among these are the Neuregulins or Heregulins. To date, four different Neuregulin genes have been identified (Neuregulin1-4) and several different splicing isoforms have been identified for at least two of these genes (Neuregulin1 and Neuregulin2). While Neuregulin1 isoforms have been extensively studied, comparatively little is known about Neuregulin3, Neuregulin4, or the Neuregulin2 isoforms. Indeed, there has been no systematic comparison of the activities of these molecules. Here we demonstrate that Neuregulin2alpha and Neuregulin2beta stimulate ErbB3 tyrosine phosphorylation and coupling to biological responses. In contrast, Neuregulin3 and Neuregulin4 fail to activate ErbB3 signaling. Furthermore, Neuregulin2beta, but not Neuregulin2alpha, stimulates ErbB4 tyrosine phosphorylation and coupling to biological responses. Finally, both Neuregulin3 and Neuregulin4 stimulate modest amounts of ErbB4 tyrosine phosphorylation. However, whereas Neuregulin3 stimulates a modest amount of ErbB4 coupling to biological responses, Neuregulin4 fails to stimulate ErbB4 coupling to biological responses. This suggests that there are qualitative as well as quantitative differences in ErbB family receptor activation by Neuregulin isoforms.

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References

  • Ballinger MD, Jones JT, Lofgren JA, Fairbrother WJ, Akita RW, Sliwkowski MX, Wells JA . 1998 J. Biol. Chem. 273: 11675–11684

  • Boonstra J, Rijken P, Humbel B, Cremers F, Verkeij A, van Bergen en Henegouwen P . 1995 Cell Biol. Intl. 19: 413–430

  • Burke CL, Stern DF . 1998 Mol. Cell. Biol. 18: 5371–5379

  • Carraway III KL, Weber JL, Unger MJ, Ledesma J, Yu N, Gassmann M, Lai C . 1997 Nature 387: 512–516

  • Chang H, Riese II DJ, Gilbert W, Stern DF, McMahan UJ . 1997 Nature 387: 509–512

  • Drummond-Barbosa D, DiMaio D . 1997 Biochim. Biophys. Acta 1332: M1–M17

  • Feroz K, Williams E, Riese II DJ . 2002 Cell. Signal. 14: 793–798

  • Groenen LC, Nice EC, Burgess AW . 1994 Growth Factors 11: 235–237

  • Gullick WJ . 2001 Endocrine-Related Cancer 8: 75–82

  • Harari D, Tzahar E, Romano J, Shelly M, Pierce JH, Andrews GC, Yarden Y . 1999 Oncogene 18: 2681–2689

  • Hijazi MM, Young PE, Dougherty MK, Bressette DS, Cao TT, Pierce JH, Wong LM, Alimandi M, King CR . 1998 Int. J. Oncol. 13: 1061–1067

  • Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard HM, Kuang W-J, Wood WI, Goeddel DV, Vandlen RL . 1992 Science 256: 1205–1210

  • Jones JT, Akita RW, Sliwkowski MX . 1999 FEBS Lett. 447: 227–231

  • Jones JT, Ballinger MD, Pisacane PI, Lofgren JA, Fitzpatrick VD, Fairbrother WJ, Wells JA, Sliwkowski MX . 1998 J. Biol. Chem. 273: 11667–11674

  • Kita YA, Barff J, Luo Y, Wen D, Brankow D, Hu S, Liu N, Prigent SA, Gullick WJ, Nicolson M . 1994 FEBS Lett. 349: 139–143

  • Klein O, Polack GW, Surti T, Kegler-Ebo D, Smith SO, DiMaio D . 1998 J. Virol. 72: 8921–8932

  • Kumar R, Vadlamudi RK . 2000 J. Clin. Ligand Assay 23: 233–237

  • Lu HS, Chang D, Philo JS, Zhang K, Narhi LO, Liu N, Zhang M, Sun J, Wen J, Yanagihara D, Karunakaran D, Yarden Y, Ratzkin B . 1995 J. Biol. Chem. 270: 4784–4791

  • Nilson LA, Gottlieb RL, Polack GW, DiMaio D . 1995 J. Virol. 69: 5869–5874

  • Normanno N, Bianco C, DeLuca A, Salomon DS . 2001 Frontiers Biosci. 6: D685–D707

  • Ozawa F, Friess H, Tempia-Caliera A, Kleeff J, Buchler MW . 2001 Teratogen. Carcinogen. Mutagen. 21: 27–44

  • Pinkas-Kramarski R, Shelly M, Glathe S, Ratzkin BJ, Yarden Y . 1996 J. Biol. Chem. 271: 19029–19032

  • Pinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I, Alamandi M, Kuo A, Moyer JD, Lavi S, Eisenstein M, Ratzkin BJ, Seger R, Bacus SS, Pierce JH, Andrews GC, Yarden Y . 1998 Mol. Cell. Biol. 18: 6090–6091

  • Pinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I, Alamandi M, Kuo A, Moyer JD, Lavi S, Eisenstein M, Ratzkin BJ, Seger R, Bacus SS, Pierce JH, Andrews GC, Yarden Y . 1999 Mol. Cell. Biol. 19: 8695

  • Plowman GD, Green JM, Culouscou J-M, Carlton GW, Rothwell VM, Buckley S . 1993 Nature 366: 473–475

  • Riese II DJ, Bermingham Y, van Raaij TM, Buckley S, Plowman GD, Stern DF . 1996a Oncogene 12: 345–353

  • Riese II DJ, Kim ED, Elenius K, Buckley S, Klagsbrun M, Plowman GD, Stern DF . 1996b J. Biol. Chem. 271: 20047–20052

  • Riese II DJ, Komurasaki T, Plowman GD, Stern DF . 1998 J. Biol. Chem. 273: 11288–11294

  • Riese II DJ, Stern DF . 1998 Bioessays 20: 41–48

  • Riese II DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF . 1995 Mol. Cell. Biol. 15: 5770–5776

  • Schlessinger J . 2000 Cell 103: 211–225

  • Stern DF . 2000 Breast Cancer Res. 2: 176–183

  • Sweeney C, Fambrough D, Huard C, Diamonti AJ, Lander ES, Cantley LC, Carraway III KL . 2001 J. Biol. Chem. 276: 22685–22698

  • Sweeney C, Lai C, Riese II DJ, Diamonti AJ, Cantley LC, Carraway III KL . 2000 J. Biol. Chem. 275: 19803–19807

  • Sweeney-Crovello C, Lai C, Cantley LC, Carraway III KL . 1998 J. Biol. Chem. 273: 26954–26961

  • Tzahar E, Levkowitz G, Karungaran D, Yi L, Peles E, Lavi S, Chang D, Liu N, Yayon A, Wen D, Yarden Y . 1994 J. Biol. Chem. 269: 25226–25233

  • Wen D, Peles E, Cupples R, Suggs SV, Bacus SS, Luo Y, Trail G, Hu S, Silbiger SM, Ben Levy R, Koski RA, Lu HS, Yarden Y . 1992 Cell 69: 559–572

  • Yarden Y, Sliwkowski MX . 2001 Nature Revs. Mol. Cell. Biol. 2: 127–137

  • Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J, Godowski PJ . 1997 Proc. Natl. Acad. Sci. USA 94: 9562–9567

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Acknowledgements

SS Hobbs was supported by an NIH predoctoral training grant (T32GM008737). EM Cameron was supported by undergraduate research fellowships from the Carroll County (Indiana) Cancer Society and the American Foundation for Pharmaceutical Education. EE Williams was supported by an undergraduate research fellowship from the American Association of Colleges of Pharmacy and Merck. RP Hammer was supported by an NIH sabbatical leave fellowship (F33CA085049). We also acknowledge additional support from the NIH (R21CA080770 to DJ Riese) the U.S. Army Medical Research and Materiel Command (DAMD17-00-1-0415 and DAMD17-00-1-0416 to DJ Riese), the Indiana Elks Foundation (to DJ Riese), and the American Cancer Society (IRG-58-006 to the Purdue Cancer Center).

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Authors and Affiliations

  1. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, 7907-1333, Indiana, IN, USA

    Stuart S Hobbs, Stephanie L Coffing, Ann TD Le, Elizabeth M Cameron, Eric E Williams, Michelle Andrew, Erika N Blommel & David J Riese II

  2. Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana, 70803-1804, LA, USA

    Robert P Hammer

  3. Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, 08543-5400, New Jersey, NJ, USA

    Han Chang

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  1. Stuart S Hobbs
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Correspondence to David J Riese II.

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Hobbs, S., Coffing, S., Le, A. et al. Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation. Oncogene 21, 8442–8452 (2002). https://doi.org/10.1038/sj.onc.1205960

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