Lessons from tumor and immunocompetent cells - The quantitative engagementof ligand-receptor interactions modulates stop-and-go behaviour as well asproliferation

The four main cell functions, proliferation, apoptosis, differentiation and migration, are tightly regulated by external signals that initiate intrace llular signal transduction pathways and determine the cellular behaviour. T he concentration and composition of such external signals are at least impo rtant for the decision of cells as to which function has to be executed. In terleukin-8 is a well known inducing signal for neutrophil granulocyte migr ation, while the epidermal growth factor is an inducing signal for breast c arcinoma cell migration. Depending on the concentrations of interleukin-8, the neutrophil granulocytes are capable of migration. However, at high conc entration of interleukin-8 the migratory activity of each single cell is re duced, indicating that high concentrations of the chemokine inhibit migrati on and promote the performance of other cell functions. Concerning breast c arcinoma cells, the epidermal growth factor is not only an inducer of migra tion but also an inhibitor of proliferation. These two examples provide evi dence for a dose dependent action of external signals for several cell func tions in parallel. This versatility of the effects of one ligand might be b ased on several intracellular signal transduction pathways that are turned on. For the dose-dependent differences of the effect of interleukin-8 we pr opose a two wheel model of an inositolphosphate-mediated, ATP-independent r elease of calcium from intracellular stores and a cyclic AMP-mediated, ATP- dependent uptake of calcium into the endoplasmatic reticulum.