Neu Differentiation Factor/Neuregulin Isoforms Activate Distinct Receptor Combinations*
- From the ‡ Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel, and
- § Amgen Center, Thousand Oaks, California 91320
- ¶ To whom correspondence should be addressed: Dept. of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel.: 972-8-9343974; Fax: 972-8-9344125; E-mail: liyarden{at}wiccmail.weizmann.ac.il
Abstract
The multiple isoforms of Neu differentiation factor (NDF/neuregulin) induce a pleiotropic cellular response that is isoform-specific and cell type-dependent. The molecular basis of this heterogeneity was addressed by comparing the two major groups of isoforms, α and β. Both groups bind to the catalytically impaired receptor tyrosine kinase ErbB-3, whose mitogenic stimulation by NDF requires transactivation by other ErbB proteins, either ErbB-1 or ErbB-2. By expressing each pair of receptors in interleukin 3-dependent myeloid cells, we found that both isoforms induced mitogenic signals in cells co-expressing the combination of ErbB-3 with ErbB-2. However, only the β isoform stimulated cells that expressed both ErbB-3 and ErbB-1, and neither isoform was active on cells expressing ErbB-3 alone. Both isoforms bind to all ErbB-3-expressing cells, albeit with different affinities, but the co-stimulatory mitogenic effect is correlated with the ability of each auxiliary receptor to transphosphorylate ErbB-3. These results imply that NDF isoforms differ in their ability to induce receptor heterodimers; whereas both types of isoforms signal through ErbB-3/ErbB-2 heterodimers, only β isoforms are able to stabilize ErbB-3/ErbB-1 heterodimers.
Footnotes
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↵* This research was supported by Grant CA51712 from the National Institutes of Health and a grant from the Forchheimer Center for Molecular Genetics. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- EGF
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epidermal growth factor
- NDF
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Neu differentiation factor
- IL
-
interleukin
- MTT
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3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide.
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- Received April 17, 1996.
- Revision received June 11, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
