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The 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. This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 50 print issues and online access 251,40 € per year only 5,03 € per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others

Aaronson SA . 1991 Science 254: 1146–1153 Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP, Kraus MH . 1995 Oncogene 10: 1813–1821 Baselga J, Mendelsohn J . 1997 J. Mam. Gland Biol. Neoplasia 2: 165–174 Baselga 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 Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes NE . 1995 Mol. Cell. Biol. 15: 6496–6505 Carter TH, Kung HJ . 1994 Crit. Rev. Oncog. 5: 389–428 Chazin VR, Kaleko M, Miller AD, Slamon DJ . 1992 Oncogene 7: 1859–1866 Chou CK, Dull TJ, Russell DS, Gherzi R, Lebwohl D, Ullrich A, Rosen OM . 1987 J. Biol. Chem. 262: 1842–1847 Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, Clinton GM . 1998 Cancer Res. 58: 5123–5129 Cobleigh 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 Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA . 1987 Science 237: 178–182 Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM . 1999 Proc. Natl. Acad. Sci. USA 96: 10869–10874 Dougall WC, Qian X, Peterson NC, Miller MJ, Samanta A, Greene MI . 1994 Oncogene 9: 2109–2123 Fantl WJ, Johnson DE, Williams LT . 1993 Ann. Rev. Biochem. 62: 453–481 Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A . 1990 Cancer Res. 50: 1550–1558 Fitzpatrick VD, Pisacane PI, Vandlen RL, Sliwkowski MX . 1998 FEBS Lett. 431: 102–106 Graus-Porta D, Beerli RR, Daly JM, Hynes NE . 1997 EMBO J. 16: 1647–1655 Graus-Porta D, Beerli RR, Hynes NE . 1995 Mol. Cell. Biol. 15: 1182–1191 Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway III KL . 1994 Proc. Natl. Acad. Sci. USA 91: 8132–8136 Hansen MB, Nielsen SE, Berg K . 1989 J. Immunol. Methods 119: 203–210 Heldin CH, Ostman A . 1996 Cytokine Growth Factor Rev. 7: 3–10 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 Hudziak RM, Lewis GD, Shalaby MR, Eessalu TE, Aggarwal BB, Ullrich A, Shepard HM . 1988 Proc. Natl. Acad. Sci. USA 85: 5102–5106 Hudziak RM, Schlessinger J, Ullrich A . 1987 Proc. Natl. Acad. Sci. USA 84: 7159–7163 Hurwitz E, Stancovski I, Sela M, Yarden Y . 1995 Proc. Natl. Acad. Sci. USA 92: 3353–3357 Hynes NE, 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, Yarden Y . 1996 EMBO J. 15: 254–264 Kashles O, Yarden Y, Fischer R, Ullrich A, Schlessinger J . 1991 Mol. Cell. Biol. 11: 1454–1463 Katsumata M, Okudaira T, Samanta A, Clark DP, Drebin JA, Jolicoeur P, Greene MI . 1995 Nat. Med. 1: 644–648 Klapper LN, Kirschbaum MH, Sela M, Yarden Y . 2000 Adv. Cancer Res. 77: 25–79 Kraus MH, Popescu NC, Amsbaugh SC, King CR . 1987 EMBO J. 6: 605–610 Lax I, Bellot F, Howk R, Ullrich A, Givol D, Schlessinger J . 1989 EMBO J. 8: 421–427 Lax I, Burgess WH, Bellot F, Ullrich A, Schlessinger J, Givol D . 1988 Mol. Cell. Biol. 8: 1831–1834 Lax I, Fischer R, Ng C, Segre J, Ullrich A, Givol D, Schlessinger J . 1991 Cell. Regul. 2: 337–345 Lemmon MA, Bu Z, Ladbury JE, Zhou M, Pinchasi D, Lax I, Engelman DM, Schlessinger J . 1997 EMBO J. 16: 281–294 Lin YZ, Clinton GM . 1991 Oncogene 6: 639–643 Lonardo F, Di Marco E, King CR, Pierce JH, Segatto O, Aaronson SA, Di Fiore, PP . 1990 New Biol. 2: 992–1003 Mendelsohn J . 1997 Clin. Cancer Res. 3: 2703–2707 Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ . 1996 Oncogene 13: 85–96 O'Rourke DM, Qian X, Zhang HT, Davis JG, Nute E, Meinkoth J, Greene MI . 1997 Proc. Natl. Acad. Sci. USA 94: 3250–3255 Olayioye MA, N RM, Lane HA, Hynes NE . 2000 EMBO J. 19: 3159–3167 Pegram 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 Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y . 1992 Cell 69: 205–216 Pinkas-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 Pinkas-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 Qian X, LeVea CM, Freeman JK, Dougall WC, Greene MI . 1994 Proc. Natl. Acad. Sci. USA 91: 1500–1504 Qian X, O'Rourke DM, Fei Z, Zhang HT, Kao CC, Greene MI . 1999 J. Biol. Chem. 274: 574–583 Qian X, O'Rourke DM, Zhao H, Greene MI . 1996 Oncogene 13: 2149–2157 Ram TG, Schelling ME, Hosick HL . 2000 Cell Growth Differ. 11: 173–183 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 Sambrook J, Fritsch EF, Maniatis T . 1989 In: Molecular Cloning. Book 3 pp 16.59 Cold Spring Harbor Laboratory Press Siegel PM, Ryan ED, Cardiff RD, Muller WJ . 1999 EMBO J. 18: 2149–2164 Slamon DJ, Clark GM . 1988 Science 240: 1795–1798 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . 1987 Science 235: 177–182 Sorkin A, Waters CM . 1993 Bioessays 15: 375–382 Spencer KS, Graus-Porta D, Leng J, Hynes NE, Klemke RL . 2000 J. Cell. Biol. 148: 385–397 Tanner KG, Kyte J . 1999 J. Biol. Chem. 274: 35985–35990 Tzahar 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 Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y . 1996 Mol. Cell. Biol. 16: 5276–5287 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, Seeburg PH . 1984 Nature 309: 418–425 Weintraub H, Cheng PF, Conrad K . 1986 Cell 46: 115–122 Woltjer RL, Lukas TJ, Staros JV . 1992 Proc. Natl. Acad. Sci. USA 89: 7801–7805 Ye D, Mendelsohn J, Fan Z . 1999 Oncogene 18: 731–738

We 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. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Azios, 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 Received: Revised: Accepted: Published: Issue date: DOI: https://doi.org/10.1038/sj.onc.1204555

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