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:

Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase

Oncogene volume 18, pages 2607–2615 (1999)Cite this article

Abstract

Receptor tyrosine kinases regulate cell behavior by activating specific signal transduction cascades. Epidermal growth factor (EGF) receptor tyrosine kinases include ErbB1, ErbB2, ErbB3 and ErbB4. ErbB4 is a tyrosine kinase receptor that binds neuregulins (NRG) and several other EGF family members. Reverse transcriptase polymerase chain reaction (RT – PCR) analysis identified two isoforms of ErbB4 that differed in their cytoplasmic domain sequences. Specifically, RT – PCR using primers flanking the putative phosphatidyl inositol 3-kinase (PI3-K) binding site of ErbB4 generated two specific bands when human and mouse heart and kidney tissues were analysed. Cloning and sequencing of these RT – PCR products revealed that one of the ErbB4 isoforms (ErbB4 CYT-2) lacked a 16 amino acid sequence including a putative PI3-K binding site, that was present in the other isoform (ErbB4 CYT-1). RT – PCR analysis of mouse tissues suggested that the expression of ErbB4 CYT-1 and ErbB4 CYT-2 was tissue-specific. Heart, breast and abdominal aorta expressed predominantly ErbB4 CYT-1 whereas neural tissues and kidney expressed predominantly ErbB4 CYT-2. To ascertain whether the absence of the putative PI3-K binding site in ErbB4 CYT-2 also resulted in the loss of PI3-K activity, NIH3T3 cell lines overexpressing ErbB4 CYT-1 or ErbB4 CYT-2 were produced. NRG-1 bound to and stimulated equivalent tyrosine phosphorylation of both isoforms. However, unlike ErbB4 CYT-1, the ErbB4 CYT-2 isoform was unable to bind the p85 subunit of PI3-K and to stimulate PI3-K activity in these cells. Furthermore, tyrosine phosphorylation of p85 or association of PI3-K activity with phosphotyrosine was not induced in NRG-1 treated cells expressing ErbB4 CYT-2, indicating that this isoform was incapable of activating PI3-K even indirectly. It was concluded that a novel naturally occurring ErbB4 isoform exists with a deletion of the cytoplasmic domain sequence required for the activation of the PI3-K intracellular signal transduction pathway and that this is the only PI3-K binding site in ErbB4.

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
Figure 8

Similar content being viewed by others

References

  • Auger KR, Serunian LA, Soltoff SP, Libby P and Cantley LC. . 1989 Cell 57: 167–175.

    Article  CAS  Google Scholar 

  • Bermingham-McDonough O, McCabe KL and Reh TA. . 1996 Development 122: 1427–1438.

  • Canoll PD, Musacchio JM, Hardy R, Reynolds R, Marchionni MA and Salzer JL. . 1996 Neuron 17: 229–243.

    Article  CAS  Google Scholar 

  • Carpenter G and Wahl MI. . 1991 In: Peptide growth factors and their receptors. Sporn MB and Roberts AB. (eds).. Springer-Verlag: New York pp. 69–171.

    Book  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Cohen BD, Green JM, Foy L and Fell HP. . 1996 J. Biol. Chem. 271: 4813–4818.

  • Culouscou JM, Carlton GW and Aruffo A. . 1995 J. Biol. Chem. 270: 12857–12863.

    Article  CAS  Google Scholar 

  • Dong Z, Brennan A, Liu N, Yarden Y, Lefkowitz G, Mirsky R and Jessen KR. . 1995 Neuron 15: 585–596.

    Article  CAS  Google Scholar 

  • Elenius K, Corfas G, Paul S, Choi CJ, Rio C, Plowman GD and Klagsbrun M. . 1997a J. Biol. Chem. 272: 26761–26768.

    Article  CAS  Google Scholar 

  • Elenius K, Paul S, Allison G, Sun J and Klagsbrun M. . 1997b EMBO J. 16: 1268–1278.

  • Falls DL, Rosen KM, Corfas G, Lane WS and Fischbach GD. . 1993 Cell 72: 801–815.

    Article  CAS  Google Scholar 

  • Franke TF, Kaplan DR and Cantley LC. . 1997 Cell 88: 435–437.

    Article  CAS  Google Scholar 

  • Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R and Lemke G. . 1995 Nature 378: 390–394.

    Article  CAS  Google Scholar 

  • Gilbertson RJ, Perry RH, Kelly PJ, Pearson ADJ and Lunec J. . 1997 Cancer Res. 57: 3272–3280.

  • Higashiyama S, Abraham JA, Miller J, Fiddes JC and Klagsbrun M. . 1991 Science 251: 936–939.

    Article  CAS  Google Scholar 

  • Higashiyama S, Horikawa M, Yamada K, Ichino N, Nakano N, Nakagawa T, Miyagawa J, Matsushita N, Nagatsu T, Taniguchi N and Ishiguro H. . 1997 J. Biochem. (Tokyo) 122: 675–680.

  • Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK and Wong AJ. . 1996 Nature 379: 560–564.

    Article  CAS  Google Scholar 

  • 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 and Vandlen RL. . 1992 Science 256: 1205–1210.

    Article  CAS  Google Scholar 

  • Hynes NE and Stern DF. . 1994 Biochim. Biophys. Acta 1198: 165–184.

  • Karunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE and Yarden Y. . 1996 EMBO J. 15: 254–264.

  • Komurasaki T, Toyoda H, Uchida D and Morimoto S. . 1997 Oncogene 15: 2841–2848.

    Article  CAS  Google Scholar 

  • Kraus MH, Issing W, Miki T, Popescu NC and Aaronson SA. . 1989 Proc. Natl. Acad. Sci. USA 86: 9193–9197.

  • Lee K-F, Simon H, Chen H, Bates B, Hung M-C and Hauser C. . 1995 Nature 378: 386–389.

    Article  CAS  Google Scholar 

  • Levkowitz G, Klapper LN, Tzahar E, Freywald A, Sela M and Yarden Y. . 1996 Oncogene 12: 1117–1125.

  • Marchionni MA, Goodearl ADJ, Chen MS, Bermingham-McDonogh O, Kirk C, Hendricks M, Danehy F, Misumi D, Sudhalter J, Kobayashi K, Wroblewski D, Lynch C, Baldassare M, Hiles I, Davis JB, Hsuan JJ, Totty NF, Otsu M, McBurney RN, Waterfield MD, Stroobant P and Gwynne D. . 1993 Nature 362: 312–318.

    Article  CAS  Google Scholar 

  • Miettinen PJ, Berger JE, Meneses J, Phung Y, Pedersen RA, Werb Z and Derynck R. . 1995 Nature 376: 337–341.

    Article  CAS  Google Scholar 

  • Moscoso LM, Chu GC, Gautam M, Noakes PG, Merlie JP and Sanes JR. . 1995 Dev. Biol. 172: 158–169.

  • Pinkas-Kramarski R, Eilam R, Spiegler O, Lavi S, Liu N, Chang D, Wen D, Schwartz M and Yarden Y. . 1994 Proc. Natl. Acad. Sci. USA 91: 9387–9391.

  • Plowman GD, Culouscou JM, Whitney GS, Green JM, Carlton GW, Foy L, Neubauer MG and Shoyab M. . 1993 Proc. Natl. Acad. Sci. USA 90: 1746–1750.

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

  • Riethmacher D, Sonnenberg-Riethmacher E, Brinkman V, Yamaai T, Lewin GR and Birchmeier C. . 1997 Nature 389: 725–730.

    Article  CAS  Google Scholar 

  • Sawyer C, Hiles I, Page M, Crompton M and Dean C. . 1998 Oncogene 17: 919–924.

    Article  CAS  Google Scholar 

  • Schlessinger J and Ullrich A. . 1992 Neuron 9: 383–391.

    Article  CAS  Google Scholar 

  • Shing Y, Christofori G, Hanahan D, Ono Y, Sasada R, Igarashi K and Folkman J. . 1993 Science 259: 1604–1607.

    Article  CAS  Google Scholar 

  • Shoyab M, Plowman GD, McDonald VL, Bradley JG and Todaro GJ. . 1989 Science 243: 1074–1076.

    Article  CAS  Google Scholar 

  • Sibilia M, Steinbach JP, Stingl L, Aguzzi A and Wagner EF. . 1998 EMBO J. 17: 719–731.

  • Sibilia M and Wagner EF. . 1995 Science 269: 234–238.

    Article  CAS  Google Scholar 

  • Soltoff SP and Cantley LC. . 1996 J. Biol. Chem. 271: 563–567.

    Article  CAS  Google Scholar 

  • Soltoff SP, Carraway KLR, Prigent SA, Gullick WG and Cantley LC. . 1994 Mol. Cell. Biol. 14: 3550–3558.

    Article  CAS  Google Scholar 

  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Fajardo JE, Chou MM, Hanafusa H, Schaffhausen B and Cantley C. . 1993 Cell 72: 767–778.

  • Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC, Barnard JA, Yuspa SH, Coffey RJ and Magnuson T. . 1995 Science 269: 230–234.

    Article  CAS  Google Scholar 

  • Toker A and Cantley LC. . 1997 Nature 387: 673–676.

    Article  CAS  Google Scholar 

  • Tokunaga K, Taniguchi Y, Yoda K, Shimizu M and Sakiyama S. . 1986 Nucleic Acids Res. 14: 2829.

  • Toyoda H, Komurasaki T, Uchida D, Takayama Y, Isobe T, Okuyama T and Hanada K. . 1995 J. Biol. Chem. 270: 7495–7500.

    Article  CAS  Google Scholar 

  • Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, Lee J, Yarden Y, Libermann TA, Schlessinger J, Downward J, Mayes ELV, Whittle N, Waterfield MD and Seeburg PH. . 1984 Nature 309: 418–425.

    Article  CAS  Google Scholar 

  • Wada T, Qian XL and Greene MI. . 1990 Cell 61: 1339–1347.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Whitman M, Kaplan DR, Schaffhausen B, Cantley L and Roberts TM. . 1985 Nature 315: 239–242.

    Article  CAS  Google Scholar 

  • Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, Saito T and Toyoshima K. . 1986 Nature 319: 230–234.

    Article  CAS  Google Scholar 

  • Yao R and Cooper GM. . 1995 Science 267: 2003–2006.

    Article  CAS  Google Scholar 

  • 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: 9562–9567.

  • Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A and Yoshinaga SK. . 1996 J. Biol. Chem. 271: 3884–3890.

    Article  CAS  Google Scholar 

  • Zhao Y-Y, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA and Kelly RA. . 1998 J. Biol. Chem. 273: 10261–10269.

    Article  CAS  Google Scholar 

  • Zimonjic DB, Alimandi M, Miki T, Popescu NC and Kraus MH. . 1995 Oncogene 10: 1235–1237.

Download references

Acknowledgements

The authors want to thank Dr Gerhard Raab for valuable discussions of the project and Pia Kuivas for excellent technical assistance. This work was supported by the Academy of Finland (KE), the Ernst Schering Research Foundation (KE and EN), the Harvard Medical School Office of Enrichment Research Fellowship (CJC), the American Heart Association (SP), the Angiogenesis Foundation (SP), the Karin Grunebaum Foundation (SP), and the NIH grants GM 47397 and CA 37392 (MK).

Author information

Authors and Affiliations

  1. Departments of Surgery and Pathology, Children's Hospital and Harvard Medical School, Boston, 02115, MA, USA

    Klaus Elenius, Caroline J Choi, Subroto Paul, Eric Santiestevan, Eiichiro Nishi & Michael Klagsbrun

  2. Medicity Research Laboratories, University of Turku, Turku, 20520, Finland

    Klaus Elenius

Authors
  1. Klaus Elenius
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline J Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Subroto Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Santiestevan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eiichiro Nishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Klagsbrun
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Elenius, K., Choi, C., Paul, S. et al. Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase. Oncogene 18, 2607–2615 (1999). https://doi.org/10.1038/sj.onc.1202612

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202612

Keywords

This article is cited by

Search

Advanced search

Quick links