Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations

Ronit Pinkas-Kramarski, Maya Shelly, Stefanie Glathe, Barry J. Ratzkin, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)19029-19032
Number of pages4
JournalJournal of Biological Chemistry
Issue number32
StatePublished - 1996
Externally publishedYes


FundersFunder number
National Cancer InstituteR01CA051712


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