Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase

Oncogene volume 23, pages 883–893 (2004)Cite this article

Abstract

The neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of peptide growth factors. These hormones are agonists for the ErbB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. We recently observed that the EGF family hormone NRG2β is a potent agonist for ErbB4. In contrast, NRG2α, a splicing isoform of the same gene that encodes NRG2β, is a poor ErbB4 agonist. We hypothesized that carboxyl-terminal residues of NRG2β are critical for stimulation of ErbB4 tyrosine phosphorylation and coupling to downstream signaling events. Here, we demonstrate that the substitution of a lysine residue for Phe45 in NRG2β results in reduced ligand potency. We also demonstrate that substitution of a phenylalanine for Lys45 in NRG2α results in increased ligand potency. Finally, analyses of the gain-of-function NRG2α Chg5 mutant demonstrate that Gln43, Met47, Asn49, and Phe50 regulate ligand efficacy. Thus, these data indicate that carboxyl-terminal residues of NRG2β are critical for activation of ErbB4 signaling. Moreover, these NRG2α and NRG2β mutants reveal new insights into models for ligand-induced ErbB family receptor tyrosine phosphorylation and coupling to downstream signaling events.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

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

  • Buonanno A and Fischbach GD . (2001). Curr. Opin. Neurobiol., 11, 287–296.

  • Burke CL and Stern DF . (1998). Mol. Cell. Biol., 18, 5371–5379.

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

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

  • Culouscou JM, Plowman GD, Carlton GW, Green JM and Shoyab M . (1993). J. Biol. Chem., 268, 18407–18410.

  • Domagala T, Konstantopoulos N, Smyth F, Jorissen RN, Fabri L, Geleick D, Lax I, Schlessinger J, Wawyer W, Howlett GJ, Burgess AW and Nice EC . (2000). Growth Factors, 18, 11–29.

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

  • Ferguson KM, Berger MB, Mendrola JM, Cho S, Leahy DJ and Lemmon M . (2003). Mol. Cell, 11, 507–517.

  • Garrett TPJ, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW and Ward CW . (2002). Cell, 110, 763–773.

  • Gullick WJ . (2001). Endocrine-Related Cancer, 8, 75–82.

  • Halgren TA . (1999). J. Comput. Chem., 20, 720–729.

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

  • Hobbs SS, Coffing SL, Le ATD, Cameron EM, Williams EE, Andrew M, Blommel EN, Hammer RP, Chang H and Riese II DJ . (2002). Oncogene, 21, 8442–8452.

  • Hoyt DW, Harkins RN, Debanne MT, O'Connor MC, Court M and Sykes BD . (1994). Biochemistry, 33, 11928–11939.

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

  • Kline TP, Brown FK, Brown SC, Jeffs B, Koppel K and Mueller L . (1990). Biochemistry, 29, 7805–7813.

  • Kohda D and Inagaki F . (1992). Biochemistry, 31, 11928–11939.

  • Lemmon MA, Bu Z, Ladbury JE, Zhou M, Pinchasi D, Lax I, Engelman DM and Schlessinger J . (1997). EMBO J., 16, 281–294.

  • Miura K, Doura H, Aizawa T, Tada H, Seno M, Yamada H and Kawano K . (2002). Biochem. Biophys. Res. Commun., 294, 1040–1046.

  • Ogiso H, Ishitani R, Nureki O, Fukai S, Yamanaka M, Kim JH, Saito K, Sakamoto A, Inoue M, Shirouzu M and Yokoyama S . (2002). Cell, 110, 775–787.

  • Penington DJ, Bryant I and Riese II DJ . (2002). Cell Growth Differ., 13, 247–256.

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

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

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

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

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

  • Schlessinger J . (2000). Cell, 103, 211–225.

  • Sherrill JM . (1997). Biochemistry, 36, 12890–12896.

  • Sherrill JM and Kyte J . (1996). Biochemistry, 35, 5705–5718.

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

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

  • van de Poll MLM, Lenferink AEG, van Vugt MJH, Jacobs JJL, Janssen JWH, Joldersma M and van Zoelen EJJ . (1995). J. Biol. Chem., 270, 22337–22343.

  • Weiss A and Schlessinger J . (1998). Cell, 94, 277–280.

  • Williams EE, Trout LJ, Gallo RM, Pitfield SE, Bryant I, Penington DJ and Riese II DJ . (2003). Cancer Lett., 192, 67–74.

  • Zhang D, Sliwkowski MX, Mark M, Frantz G, Akita R, Sun Y, Hillan K, Crowley C, Brush J and Godowski PJ . (1997). Proc. Natl. Acad. Sci. USA, 94, 9562–9667.

Download references

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. RP Hammer was supported by an NIH sabbatical leave fellowship (F33CA085049). We acknowledge additional support from the NIH (R21CA080770 and R21CA089274 to DJR), the US Army Medical Research and Materiel Command (DAMD17-00-1-0415, DAMD17-00-1-0416, and DAMD17-02-1-0130 to DJR), the Indiana Elks Foundation (to DJR) and American Cancer Society (IRG-58-006 to the Purdue Cancer Center).

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, 47907-2064, IN, USA

    Stuart S Hobbs, Elizabeth M Cameron, Ann T D Le, Richard M Gallo, Erika N Blommel, Stephanie L Coffing & David J Riese II

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

    Robert P Hammer

  3. Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, 08543-5400, NJ, USA

    Han Chang

Authors
  1. Stuart S Hobbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth M Cameron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert P Hammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ann T D Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Richard M Gallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erika N Blommel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephanie L Coffing
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Han Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David J Riese II
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David J Riese II.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hobbs, S., Cameron, E., Hammer, R. et al. Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase. Oncogene 23, 883–893 (2004). https://doi.org/10.1038/sj.onc.1207250

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207250

Keywords

Search

Advanced search

Quick links