9723897 Wofsy Methods of mathematics and statistics, in conjunction with experimental work in two cell biology laboratories, will be used to clarify the early biophysical and biochemical events that occur when extracellular signaling molecules interact with specific receptors on cell surfaces, to initiate and regulate cellular responses. Common features of cell signaling in different physiological systems have emerged from intensive experimental work over the past decade. In general, the extracellular signaling molecules induce the aggregation of cell surface receptors, and for many receptors, the first detectable cellular response to receptor aggregation is the phosphorylation of the amino acid tyrosine on the receptor and other cellular proteins. Intracellular enzymes then interact with the newly phosphorylated sites and mediate further biochemical and cellular responses. The proposed work attempts to clarify the initial events in the signaling cascade: receptor aggregation and tyrosine phsophorylation, for the multi-subunit receptors of the immune system. Part of the work involves analysis of point patterns on newly available cell surface images, reflecting the spatial distribution of cell surface receptors. This project continues a collaboration designed to use such images quantitatively to make inferences about the mechanisms and effects of receptor aggregation. The development and application of additional statistical methods of point pattern analysis to understand the relationship between different aggregation states and cellular responses will also be done. The second collaboration addresses mechanisms by which aggregated receptors mediate the phosphorylation of tyrosine on receptors and other substrates. These studies will provide models for the mechanisms of the early events in cell signaling, which should lead to experiments that can test them. %%% A number of cell surface receptors respond to ligand binding by aggregation, which is then followed by phospho rylation of tyrosine residues in the receptor and other cellular proteins. The research here will use mathematical modeling of experimental systems to clarify these initial events in the signaling cascade for receptors of the immune system. ***
