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PMID: 8096177 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Cell-type specific interaction of Neu differentiation factor (NDF/heregulin) with Neu/HER-2 suggests complex ligand-receptor relationships.

The EMBO journal ·Vol. 12 ·No. 3 ·1993-03-00 ·Pages 961-71

Peles E, Ben-Levy R, Tzahar E, Liu N, Wen D, Yarden Y

Abstract

The Neu/HER-2 receptor tyrosine kinase is overexpressed in some types of human adenocarcinomas, including tumors of the breast and the ovary. A 44 kDa glycoprotein that elevates tyrosine phosphorylation of Neu has been isolated and named Neu differentiation factor (NDF), or heregulin. Here we show that NDF affects tyrosine phosphorylation of Neu in human tumor cells of breast, colon and neuronal origin, but not in ovarian cells that overexpress the receptor. By using monoclonal antibodies (mAbs) to Neu, we found that the ovarian receptor is immunologically and biochemically similar to the mammary p185neu. Nevertheless, unlike breast-derived Neu, the ovarian protein did not display covalent cross-linking to radiolabeled NDF, and was devoid of ligand-induced association with phosphatidylinositol 3'-kinase. Direct binding analysis showed that NDF binds with high affinity (Kd approximately 10(-9) M) to mammary cells, but its weak association with ovarian cells is probably mediated by heparin-like molecules. Similar to the endogenous receptor, the ectopically overexpressed Neu of mammary cells, but not of ovarian and fibroblastic cells, exhibited elevated levels of NDF-induced phosphorylation and covalent cross-linking of the radiolabeled factor. Taken together, our results imply that NDF binding to cells requires both Neu and an additional cellular component, whose identity is still unknown, but its tissue distribution is more restricted than the expression of the neu gene.

MeSH Terms
Animals Antibodies, Monoclonal Breast Neoplasms Cross-Linking Reagents Female Glycoproteins/metabolism Humans Ligands Mice Neuregulins Ovarian Neoplasms Phosphatidylinositol 3-Kinases Phosphorylation Phosphotransferases/metabolism Protein-Tyrosine Kinases/metabolism Proto-Oncogene Proteins/immunology,metabolism Rats Receptor, ErbB-2 Signal Transduction Tumor Cells, Cultured
Chemicals
Antibodies, Monoclonal Cross-Linking Reagents Glycoproteins Ligands Neuregulins Proto-Oncogene Proteins Phosphotransferases Phosphatidylinositol 3-Kinases Protein-Tyrosine Kinases Receptor, ErbB-2
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Peles E
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Ben-Levy R
Tzahar E
Liu N
Wen D
Yarden Y
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1993-03-00
Pages
961-71
Language
English
Region
England
NLM ID
8208664
PMCID
PMC413297
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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