Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 96 (19): 10869-10874

Copyright © 1999 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor

Joni K. Doherty*,{dagger}, Chris Bond{ddagger}, Armando Jardim§, John P. Adelman{ddagger}, and Gail M. Clinton§

Departments of *Cell and Developmental Biology and §Biochemistry and Molecular Biology, and {ddagger}The Vollum Institute, Oregon Health Sciences University, Portland, OR 97201

Accepted for publication July 12, 1999.

Received for publication April 14, 1999.

Abstract: HER-2/neu (erbB-2) encodes an 185-kDa orphan receptor tyrosine kinase that is constitutively active as a dimer and displays potent oncogenic activity when overexpressed. Here we describe a secreted protein of {approx}68 kDa, designated herstatin, as the product of an alternative HER-2 transcript that retains intron 8. This alternative transcript specifies 340 residues identical to subdomains I and II from the extracellular domain of p185HER-2 followed by a unique C-terminal sequence of 79 aa encoded by intron 8. The recombinant product of the alternative transcript specifically binds to HER-2-transfected cells with a KD of {approx}14 nM and was chemically crosslinked to p185HER-2, whereas the intron encoded sequence alone also binds with high affinity to transfected cells and associates with p185 solubilized from cell extracts. The herstatin mRNA is expressed in normal human fetal kidney and liver, but is at reduced levels relative to p185HER-2 mRNA in carcinoma cells that contain an amplified HER-2 gene. Herstatin appears to be an inhibitor of p185HER-2, because it disrupts dimers, reduces tyrosine phosphorylation of p185, and inhibits the anchorage-independent growth of transformed cells that overexpress HER-2.


{dagger} Present address: Department of Otolaryngology, Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033.

To whom reprint requests should be addressed at: L224 Basic Science Building, 3181 SW Sam Jackson Park Road, Portland, OR 97201. E-mail: clinton{at}ohsu.edu.

Communicated by Tony Hunter, The Salk Institute for Biological Studies, San Diego, CA

Database deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF177761).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Suppression of Heregulin {beta} Signaling by the Single N-Glycan Deletion Mutant of Soluble ErbB3 Protein.
M. Takahashi, Y. Hasegawa, Y. Ikeda, Y. Wada, M. Tajiri, S. Ariki, R. Takamiya, C. Nishitani, M. Araki, Y. Yamaguchi, et al. (2013)
J. Biol. Chem. 288, 32910-32921
   Abstract »    Full Text »    PDF »
HER-2 Protein Overexpressing Breast Cancer Without Gene Amplification Shows Higher Hormone Receptor Expression Than HER-2 Protein Overexpressing Breast Cancer With Gene Amplification.
J. S. Koo, W. Jung, and W. I. Yang (2011)
International Journal of Surgical Pathology 19, 425-432
   Abstract »    PDF »
Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy.
M Hofmann, O Stoss, T Gaiser, H Kneitz, P Heinmoller, T Gutjahr, M Kaufmann, T Henkel, and J Ruschoff (2008)
J. Clin. Pathol. 61, 89-94
   Abstract »    Full Text »    PDF »
Therapeutic potential of epidermal growth factor receptor-related protein..
J. L. Reiter, N. J. Maihle, and G. M. Clinton (2006)
Mol. Cancer Ther. 5, 2954
   Full Text »    PDF »
p95HER-2 Predicts Worse Outcome in Patients with HER-2-Positive Breast Cancer.
R. Saez, M. A. Molina, E. E. Ramsey, F. Rojo, E. J. Keenan, J. Albanell, A. Lluch, J. Garcia-Conde, J. Baselga, and G. M. Clinton (2006)
Clin. Cancer Res. 12, 424-431
   Abstract »    Full Text »    PDF »
Herstatin, an Autoinhibitor of the Epidermal Growth Factor (EGF) Receptor Family, Blocks the Intracranial Growth of Glioblastoma.
J. A. Staverosky, L. L. Muldoon, S. Guo, A. J. Evans, E. A. Neuwelt, and G. M. Clinton (2005)
Clin. Cancer Res. 11, 335-340
   Abstract »    Full Text »    PDF »
Intron Retention Generates a Novel Id3 Isoform That Inhibits Vascular Lesion Formation.
S. T. Forrest, K. G. Barringhaus, D. Perlegas, M.-L. Hammarskjold, and C. A. McNamara (2004)
J. Biol. Chem. 279, 32897-32903
   Abstract »    Full Text »    PDF »
Negative Regulation of HER2 Signaling by the PEST-type Protein-tyrosine Phosphatase BDP1.
M. Gensler, M. Buschbeck, and A. Ullrich (2004)
J. Biol. Chem. 279, 12110-12116
   Abstract »    Full Text »    PDF »
Soluble Epidermal Growth Factor Receptor (sEGFR/sErbB1) as a Potential Risk, Screening, and Diagnostic Serum Biomarker of Epithelial Ovarian Cancer.
A. T. Baron, E. M. Cora, J. M. Lafky, C. H. Boardman, M. C. Buenafe, A. Rademaker, D. Liu, D. A. Fishman, K. C. Podratz, and N. J. Maihle (2003)
Cancer Epidemiol. Biomarkers Prev. 12, 103-113
   Abstract »    Full Text »    PDF »
Active Signaling by HER-2/neu in a Subpopulation of HER-2/neu-overexpressing Ductal Carcinoma in Situ: Clinicopathological Correlates.
M. P. DiGiovanna, P. Chu, T. L. Davison, C. L. Howe, D. Carter, E. B. Claus, and D. F. Stern (2002)
Cancer Res. 62, 6667-6673
   Abstract »    Full Text »    PDF »
Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics.
A. Berezov, J. Chen, Q. Liu, H.-T. Zhang, M. I. Greene, and R. Murali (2002)
J. Biol. Chem. 277, 28330-28339
   Abstract »    Full Text »    PDF »
Herstatin, an Autoinhibitor of the Human Epidermal Growth Factor Receptor 2 Tyrosine Kinase, Modulates Epidermal Growth Factor Signaling Pathways Resulting in Growth Arrest.
Q. A. Justman and G. M. Clinton (2002)
J. Biol. Chem. 277, 20618-20624
   Abstract »    Full Text »    PDF »
A Naturally Occurring Secreted Human ErbB3 Receptor Isoform Inhibits Heregulin-stimulated Activation of ErbB2, ErbB3, and ErbB4.
H. Lee, R. W. Akita, M. X. Sliwkowski, and N. J. Maihle (2001)
Cancer Res. 61, 4467-4473
   Abstract »    Full Text »    PDF »
The role of distinct p185neu extracellular subdomains for dimerization with the epidermal growth factor (EGF) receptor and EGF-mediated signaling.
T. Kumagai, J. G. Davis, T. Horie, D. M. O'Rourke, and M. I. Greene (2001)
PNAS 98, 5526-5531
   Abstract »    Full Text »    PDF »
Aspartyl {beta}-Hydroxylase (Asph) and an Evolutionarily Conserved Isoform of Asph Missing the Catalytic Domain Share Exons with Junctin.
J. E. Dinchuk, N. L. Henderson, T. C. Burn, R. Huber, S. P. Ho, J. Link, K. T. O'Neil, R. J. Focht, M. S. Scully, J. M. Hollis, et al. (2000)
J. Biol. Chem. 275, 39543-39554
   Abstract »    Full Text »    PDF »
Activation (Tyrosine Phosphorylation) of ErbB-2 (HER-2/neu): A Study of Incidence and Correlation With Outcome in Breast Cancer.
A. D. Thor, S. Liu, S. Edgerton, D. Moore II, K. M. Kasowitz, C. C. Benz, D. F. Stern, and M. P. DiGiovanna (2000)
J. Clin. Oncol. 18, 3230-3239
   Abstract »    Full Text »    PDF »
Geldanamycin Induces ErbB-2 Degradation by Proteolytic Fragmentation.
O. Tikhomirov and G. Carpenter (2000)
J. Biol. Chem. 275, 26625-26631
   Abstract »    Full Text »    PDF »
Aspartyl beta-hydroxylase (Asph)and an evolutionarily conserved isoform of Asph missing the catalytic domain share exons with junctin.
J. E. Dinchuk, N. L. Henderson, T. C. Burn, R. Huber, S. P. Ho, J. Link, K. T. O'Neil, R. J. Focht, M. S. Scully, J. M. Hollis, et al. (2000)
J. Biol. Chem.
   Abstract »
The role of distinct p185neu extracellular subdomains for dimerization with the epidermal growth factor (EGF) receptor and EGF-mediated signaling.
T. Kumagai, J. G. Davis, T. Horie, D. M. O'Rourke, and M. I. Greene (2001)
PNAS 98, 5526-5531
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882