Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations.
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.
Pinkas-Kramarski
R
R
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Shelly
M
M
Glathe
S
S
Ratzkin
B J
BJ
Yarden
Y
Y
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D007536:Isomerism; D051379:Mice; D020880:Neuregulins; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3; D015533:Transcriptional Activation
D006023:Glycoproteins; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D020893:Receptor, ErbB-3