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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.
The Journal of Biological Chemistry
|August 9, 1996
Summary
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.