{"paper_id":"899b8ccd-11db-406a-9a2d-7d6581982ad3","body_text":"Abstract\nThe four members of the EGF receptor family are capable of homomeric as well as heteromeric interactions. HER-2/neu (erbB-2) dominates as the preferred coreceptor that amplifies mitogenic signaling. An alternative HER-2/neu product, herstatin, consists of a segment of the ectodomain of p185HER-2 and an intron-encoded C-terminus. Recombinant herstatin was found to bind with nM affinity and inhibit p185HER-2. To further examine the impact on receptor activity, herstatin was expressed with various receptor tyrosine kinases. In CHO cells that overexpressed HER-2, herstatin caused a sevenfold inhibition of colony formation that corresponded to a reduction in the tyrosine phosphorylation of p185HER-2. Herstatin also prevented HER-2 mediated transactivation of the kinase impaired HER-3 as reflected in transphosphorylation of HER-3 and heteromers between HER-2 and HER-3. In EGF receptor-overexpressing cells, EGF induction of receptor dimerization and tyrosine phosphorylation were reduced more than 90%, and receptor down-regulation as well as colony formation were also suppressed by coexpression with herstatin. Inhibition was selective for the EGF receptor family since herstatin expression did not reduce tyrosine phosphorylation mediated by the FGF receptor-2 or by insulin-like growth factor -1. Herstatin bound to the EGF receptor as well as to p185HER-2 in pull-down assays suggesting that complex formation may be involved in receptor inhibition. Our findings indicate that herstatin has the capability to negatively regulate combinations of interactions between group I receptor tyrosine kinases that confer synergistic growth signals.\nThis is a preview of subscription content, access via your institution\nAccess options\nSubscribe to this journal\nReceive 50 print issues and online access\n251,40 € per year\nonly 5,03 € per issue\nBuy this article\n- Purchase on SpringerLink\n- Instant access to the full article PDF.\n39,95 €\nPrices may be subject to local taxes which are calculated during checkout\nSimilar content being viewed by others\nReferences\nAaronson SA . 1991 Science 254: 1146–1153\nAlimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP, Kraus MH . 1995 Oncogene 10: 1813–1821\nBaselga J, Mendelsohn J . 1997 J. Mam. Gland Biol. Neoplasia 2: 165–174\nBaselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L . 1996 J. Clin. Oncol. 14: 737–744\nBeerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes NE . 1995 Mol. Cell. Biol. 15: 6496–6505\nCarter TH, Kung HJ . 1994 Crit. Rev. Oncog. 5: 389–428\nChazin VR, Kaleko M, Miller AD, Slamon DJ . 1992 Oncogene 7: 1859–1866\nChou CK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A, Rosen OM . 1987 J. Biol. Chem. 262: 1842–1847\nChristianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, Clinton GM . 1998 Cancer Res. 58: 5123–5129\nCobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ . 1999 J. Clin. Onco. 17: 2639–2648\nDi Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA . 1987 Science 237: 178–182\nDoherty JK, Bond C, Jardim A, Adelman JP, Clinton GM . 1999 Proc. Natl. Acad. Sci. USA 96: 10869–10874\nDougall WC, Qian X, Peterson NC, Miller MJ, Samanta A, Greene MI . 1994 Oncogene 9: 2109–2123\nFantl WJ, Johnson DE, Williams LT . 1993 Ann. Rev. Biochem. 62: 453–481\nFendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A . 1990 Cancer Res. 50: 1550–1558\nFitzpatrick VD, Pisacane PI, Vandlen RL, Sliwkowski MX . 1998 FEBS Lett. 431: 102–106\nGraus-Porta D, Beerli RR, Daly JM, Hynes NE . 1997 EMBO J. 16: 1647–1655\nGraus-Porta D, Beerli RR, Hynes NE . 1995 Mol. Cell. Biol. 15: 1182–1191\nGuy PM, Platko JV, Cantley LC, Cerione RA, Carraway III KL . 1994 Proc. Natl. Acad. Sci. USA 91: 8132–8136\nHansen MB, Nielsen SE, Berg K . 1989 J. Immunol. Methods 119: 203–210\nHeldin CH, Ostman A . 1996 Cytokine Growth Factor Rev. 7: 3–10\nHolmes 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\nHudziak RM, Lewis GD, Shalaby MR, Eessalu TE, Aggarwal BB, Ullrich A, Shepard HM . 1988 Proc. Natl. Acad. Sci. USA 85: 5102–5106\nHudziak RM, Schlessinger J, Ullrich A . 1987 Proc. Natl. Acad. Sci. USA 84: 7159–7163\nHurwitz E, Stancovski I, Sela M, Yarden Y . 1995 Proc. Natl. Acad. Sci. USA 92: 3353–3357\nHynes NE, Stern DF . 1994 Biochim. Biophys. Acta 1198: 165–184\nKarunagaran D, Tzahar E, Beerli RR, Chen X, Graus-Porta D, Ratzkin BJ, Seger R, Hynes NE, Yarden Y . 1996 EMBO J. 15: 254–264\nKashles O, Yarden Y, Fischer R, Ullrich A, Schlessinger J . 1991 Mol. Cell. Biol. 11: 1454–1463\nKatsumata M, Okudaira T, Samanta A, Clark DP, Drebin JA, Jolicoeur P, Greene MI . 1995 Nat. Med. 1: 644–648\nKlapper LN, Kirschbaum MH, Sela M, Yarden Y . 2000 Adv. Cancer Res. 77: 25–79\nKraus MH, Popescu NC, Amsbaugh SC, King CR . 1987 EMBO J. 6: 605–610\nLax I, Bellot F, Howk R, Ullrich A, Givol D, Schlessinger J . 1989 EMBO J. 8: 421–427\nLax I, Burgess WH, Bellot F, Ullrich A, Schlessinger J, Givol D . 1988 Mol. Cell. Biol. 8: 1831–1834\nLax I, Fischer R, Ng C, Segre J, Ullrich A, Givol D, Schlessinger J . 1991 Cell. Regul. 2: 337–345\nLemmon MA, Bu Z, Ladbury JE, Zhou M, Pinchasi D, Lax I, Engelman DM, Schlessinger J . 1997 EMBO J. 16: 281–294\nLin YZ, Clinton GM . 1991 Oncogene 6: 639–643\nLonardo F, Di Marco E, King CR, Pierce JH, Segatto O, Aaronson SA, Di Fiore, PP . 1990 New Biol. 2: 992–1003\nMendelsohn J . 1997 Clin. Cancer Res. 3: 2703–2707\nMoscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ . 1996 Oncogene 13: 85–96\nO'Rourke DM, Qian X, Zhang HT, Davis JG, Nute E, Meinkoth J, Greene MI . 1997 Proc. Natl. Acad. Sci. USA 94: 3250–3255\nOlayioye MA, N RM, Lane HA, Hynes NE . 2000 EMBO J. 19: 3159–3167\nPegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ . 1998 J. Clin. Onco. 16: 2659–2671\nPeles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y . 1992 Cell 69: 205–216\nPinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I, Alimandi M, Kuo A, Moyer JD, Lavi S, Eisenstein M, Ratzkin BJ, Seger R, Bacus SS, Pierce JH, Andrews GC, Yarden Y, Alamandi M . 1998 Mol. Cell. Biol. 18: 6090–6101\nPinkas-Kramarski R, Soussan L, Waterman H, Levkowitz G, Alroy I, Klapper L, Lavi S, Seger R, Ratzkin BJ, Sela M, Yarden Y . 1996 EMBO J. 15: 2452–2467\nQian X, LeVea CM, Freeman JK, Dougall WC, Greene MI . 1994 Proc. Natl. Acad. Sci. USA 91: 1500–1504\nQian X, O'Rourke DM, Fei Z, Zhang HT, Kao CC, Greene MI . 1999 J. Biol. Chem. 274: 574–583\nQian X, O'Rourke DM, Zhao H, Greene MI . 1996 Oncogene 13: 2149–2157\nRam TG, Schelling ME, Hosick HL . 2000 Cell Growth Differ. 11: 173–183\nRiese II DJ, Stern DF . 1998 Bioessays 20: 41–48\nRiese II DJ, van Raaij TM, Plowman GD, Andrews GC, Stern DF . 1995 Mol. Cell. Biol. 15: 5770–5776\nSambrook J, Fritsch EF, Maniatis T . 1989 In: Molecular Cloning. Book 3 pp 16.59 Cold Spring Harbor Laboratory Press\nSiegel PM, Ryan ED, Cardiff RD, Muller WJ . 1999 EMBO J. 18: 2149–2164\nSlamon DJ, Clark GM . 1988 Science 240: 1795–1798\nSlamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . 1987 Science 235: 177–182\nSorkin A, Waters CM . 1993 Bioessays 15: 375–382\nSpencer KS, Graus-Porta D, Leng J, Hynes NE, Klemke RL . 2000 J. Cell. Biol. 148: 385–397\nTanner KG, Kyte J . 1999 J. Biol. Chem. 274: 35985–35990\nTzahar E, Pinkas-Kramarski R, Moyer JD, Klapper LN, Alroy I, Levkowitz G, Shelly M, Henis S, Eisenstein M, Ratzkin BJ, Sela M, Andrews GC, Yarden Y . 1997 EMBO J. 16: 4938–4950\nTzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y . 1996 Mol. Cell. Biol. 16: 5276–5287\nUllrich 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, Seeburg PH . 1984 Nature 309: 418–425\nWeintraub H, Cheng PF, Conrad K . 1986 Cell 46: 115–122\nWoltjer RL, Lukas TJ, Staros JV . 1992 Proc. Natl. Acad. Sci. USA 89: 7801–7805\nYe D, Mendelsohn J, Fan Z . 1999 Oncogene 18: 731–738\nAcknowledgements\nWe acknowledge Adam Evans and John Adelman for critically reading the manuscript. We thank Mark Greene for providing the T691neu mutant and Tracy Ram for the HER-3 expression plasmid. This study was supported by grants from the National Cancer Institute, NCI.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nRights and permissions\nAbout this article\nCite this article\nAzios, N., Romero, F., Denton, M. et al. Expression of herstatin, an autoinhibitor of HER-2/neu, inhibits transactivation of HER-3 by HER-2 and blocks EGF activation of the EGF receptor. Oncogene 20, 5199–5209 (2001). https://doi.org/10.1038/sj.onc.1204555\nReceived:\nRevised:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1038/sj.onc.1204555\nKeywords\nThis article is cited by\n-\nThe Peptide Derived from erbB2 Auto-Inhibitor Herstatin Shared in the Same Epitope and Function with Functional Antibody 2C4\nMolecular Biotechnology (2012)\n-\nThe ERBB3 receptor in cancer and cancer gene therapy\nCancer Gene Therapy (2008)\n-\nAn intron with a constitutive transport element is retained in a Tap messenger RNA\nNature (2006)","source_license":"CC0","license_restricted":false}