RECEPTOR AGGREGATION ON THE CELL SURFACE

The binding of a ligand to a cell surface receptor is the first step in a
cascade of events that leads to the generation of a transmembrane signal.
In many cell systems, simple ligand binding is insufficient to initiate
signal transduction, rather, receptor aggregation is required. On the
surface of mast cells, basophils and rat basophilic leukemia (RBL) cells
are Fc receptors (Fc-epsilon-RI) which bind IgE with high affinity. The
formation of aggregates of IgE or equivalently of the Fc-epsilon-RI
receptors triggers various cellular responses. However, it is not clear
what physical and steric conditions must be met by the IgE-receptor
aggregates in order to initiate signal transduction. The goal of this
project is to understand receptor aggregation in general and in particular
to determine the properties of an IgE-receptor aggregate that are required
to initiate particular cellular responses. To do this we will use
multiparameter flow cytometry to simultaneously measure the kinetics of
ligand binding and crosslinking of cell surface IgE with changes in
intracellular Ca2+ levels. We will develop and test mathematical models
that predict the time course of the IgE aggregate distribution that is
formed when surface IgE is crosslinked by these ligands and relate this
aggregation to cellular responses. We expect that the results of these
studies can be generalized to other receptor systems in which receptor
aggregation is involved in signal transduction. The studies in this
project are health related bearing on allergic reactions as well as ligand
receptor reactions in general.