NDF HEREGULIN ACTIVATES MAP KINASE AND P70 P85 S6 KINASE DURING PROLIFERATION OR DIFFERENTIATION OF MAMMARY EPITHELIAL-CELLS/

Neu differentiation factors (NDF) are a novel family of polypeptide fa ctors which activate sub-class I tyrosine kinase receptors. In all mam mary epithelial cells analysed in this study, NDF activates the same s ignalling pathways while it induces different, cell-specific biologica l effects. In AU565 cells which are growth inhibited, as well as in T4 7D or HC11 cells which proliferate in response to NDF, the MAP kinase isoforms p44(ERK1) and p42(ERK2) and the p70/p85 S6 kinase are activat ed. NDF stimulates tyrosine phosphorylation and the in vitro kinase ac tivity of ErbB-2. When PKC is activated by TPA, NDF is no longer able to activate ErbB-2 in T47D cells, leading to a blockage of cell prolif eration. Activation of ErbB-2 by point mutation, or by monoclonal anti bodies, also stimulates both the MAPK and the p70/p85 S6 kinase pathwa ys. The same monoclonal antibodies can induce AU565 cell differentiati on. In summary, during growth or differentiation of mammary epithelial cells, NDF stimulates several independent signalling pathways which c an also be triggered by ErbB-2 stimulation alone. PKC activation block s the biological effect induced by NDF through negative modulation of ErbB-2.