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PNAS 96 (19): 10869-10874

Copyright © 1999 by the National Academy of Sciences.

Vol. 96, Issue 19, 10869-10874, September 14, 1999

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

Joni K. Doherty*,dagger , Chris BondDagger , Armando Jardim§, John P. AdelmanDagger , and Gail M. Clinton§,

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

Communicated by Tony Hunter, The Salk Institute for Biological Studies, San Diego, CA, July 12, 1999 (received for review April 14, 1999)

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.

Copyright © 1999 by The National Academy of Sciences  0027-8424/99/9610869-6$2.00/0

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