Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2

The neuregulins comprise a subfamily of epidermal growth factor (EGF)-like growth factors that elicit diverse cellular responses by activating members of the ErbB family of receptor tyrosine kinases. Although neuregulin-1 and neuregulin-2 are both binding ligands for the ErbB3 and ErbB4 receptors, they exhibit distinct biological activities depending on cellular context. In MDA-MB-468 human mammary tumor cells, neuregulin-2beta (NRG2beta) inhibits cell growth, whereas neuregulin-1beta (NRG1beta) does not. In these cells, NRG2beta appears to preferentially act through the EGF receptor, stimulating receptor tyrosine phosphorylation and the recruitment of phospholipase C-gamma, Cbl, SHP2, and Shc to that receptor. NRG1beta preferentially acts through ErbB3 in these cells by stimulating the tyrosine phosphorylation and recruitment of phosphatidylinositol 3-kinase and Shc to that receptor. In MDA-MB-453 cells, both NRG1beta and NRG2beta stimulate the tyrosine phosphorylation of the ErbB2 and ErbB3 receptors to similar extents, but only NRG1beta potently stimulates morphological changes consistent with their differentiation. The profiles of SH2 domain-containing proteins that are efficiently recruited to activated receptors differ for the two factors. These observations indicate that despite their overlapping receptor specificity, the neuregulins exhibit distinct biological and biochemical properties. Since both of these cell lines express only two of the known ErbB receptors, our results imply that EGF-like ligands might elicit differential signaling within the context of a single receptor heterodimer.