NEU DIFFERENTIATION FACTOR NEUREGULIN ISOFORMS ACTIVATE DISTINCT RECEPTOR COMBINATIONS

The multiple isoforms of Neu differentiation factor (NDF/neuregulin) i nduce a pleiotropic cellular response that is isoform-specific and cel l type-dependent. The molecular basis of this heterogeneity was addres sed by comparing the two major groups of isoforms, alpha and beta. Bot h groups bind to the catalytically impaired receptor tyrosine kinase E rbB-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 S-dependent myeloid cells, we found that b oth isoforms induced mitogenic signals in cells co-expressing the comb ination of ErbB-3 with ErbB-2. However, only the beta isoform stimulat ed cells that expressed both ErbB-3 and ErbB-1, and neither isoform wa s active on cells expressing ErbB-3 alone. Both isoforms bind to all E rbB-3-expressing cells, albeit with different affinities, but the co-s timulatory mitogenic effect is correlated with the ability of each aux iliary 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 heterodim ers, only beta isoforms are able to stabilize ErbB-3/ErbB-1 heterodime rs.