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Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations
R Pinkas-Kramarski1, M Shelly, S Glathe
1Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
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, alpha and beta. 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 beta 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 beta isoforms are able to stabilize ErbB-3/ErbB-1 heterodimers.
Insights
Neu differentiation factor (NDF/neuregulin) isoforms exhibit cell-specific signaling through ErbB receptor interactions. NDF alpha and beta isoforms differentially activate ErbB-3/ErbB-2 and ErbB-3/ErbB-1 heterodimers, influencing cellular responses.
Area of Science:
- Cellular and Molecular Biology
- Receptor Tyrosine Kinase Signaling
- Signal Transduction
Background:
- Neu differentiation factor (NDF/neuregulin) isoforms elicit diverse cellular responses.
- The molecular mechanisms underlying NDF isoform-specific signaling are not fully understood.
Purpose of the Study:
- To investigate the molecular basis for the differential cellular responses induced by NDF alpha and beta isoforms.
- To elucidate the role of ErbB receptor heterodimerization in NDF-mediated signaling.
Main Methods:
- Expression of specific ErbB receptor pairs (ErbB-3 with ErbB-1 or ErbB-2) in interleukin 3-dependent myeloid cells.
- Assessment of NDF isoform binding affinities and mitogenic signaling.
- Analysis of ErbB-3 transphosphorylation and heterodimer formation.
Main Results:
- Both NDF alpha and beta isoforms induced mitogenic signals in cells co-expressing ErbB-3 and ErbB-2.
- Only NDF beta isoforms stimulated cells co-expressing ErbB-3 and ErbB-1.
- NDF isoforms bind ErbB-3 expressing cells with varying affinities, and signaling correlates with receptor transphosphorylation.
Conclusions:
- NDF isoforms exhibit distinct abilities to stabilize ErbB-3/ErbB-1 and ErbB-3/ErbB-2 heterodimers.
- The differential stabilization of receptor heterodimers by NDF isoforms underlies their isoform-specific and cell-dependent signaling.
- These findings provide insight into the complex regulation of cellular responses by NDF.