Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells

Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185(c-erbB-2), recent evidence suggests that other receptors of the erbB family, including p180(erbB-3) and p180(erbB-4), are their true cognate receptors. Stimulation of MDA MB-453 cells with HRGβ2 resulted in the tyrosine phosphorylation of p185(c-erbB-2), and p180(erbB-4) in a time-and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185(c-erbB-2) and p180(erbB-4). In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185(c-erbB-2), p180(erbB-4) and SHC. Activation of mitogen-activated protein kinase (MAPR) (> 30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos (> 200-fold). These observations suggest that p21(ras) activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185(c-erbB-2) and p180(erbB-4), revealed a preferential association with activated p180(erbB-4). These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained.