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

Joni K. Doherty, Chris Bond, Armando Jardim, John P. Adelman, Gail M. Clinton

Research output: Contribution to journalArticle

99 Scopus citations

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 ≃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 ≃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.

Original languageEnglish (US)
Pages (from-to)10869-10874
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number19
DOIs
StatePublished - Sep 14 1999

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