ABSTRACT Biological membranes create compartments within cells and demarcate the outsides of cells from their insides. Beyond their role as physical barriers, lipid membranes also are used as platforms to organize biological processes essential for life: Membrane surfaces are unique for the exceptional ability to coalesce, organize, and regulate biological complexes necessary to transmit information between cells and among cellular compartments. Certain of these biological complexes are core nodes that coordinate diverse inputs into conserved outputs. One such core node is organized and orchestrated by the phospholipase C gamma (PLC-) isozymes in response to diverse transmembrane receptors including a host of receptor tyrosine kinases and immune receptors. We will study this core node as a “Rosetta Stone” to learn the inherent and emergent properties of signaling at biological membranes. By systematically and quantitatively comparing how properties of this core node and associated cellular responses are altered for different classes of input receptors and in different cell types, we will derive fundamental and guiding principles about how cells and tissues execute precise signaling within the physical-chemical constraints of their biological membranes. This goal will be accomplished using a highly collaborative and interdisciplinary approach: Detailed structural, biophysical, and biochemical studies of purified proteins and complexes will guide complementary studies of reconstituted nodes on self- assembled lipid bilayers or re-engineered in cells to be controlled and imaged with light. Data from these studies will inform computational models based on a newly-developed frameworks describing core nodes operating at membranes that will be used to predict signaling kinetics, efficiency, and dynamics in response to changes in core components, inputs, and feedback regulation. Together, these studies will reveal critical insights into the function and regulation of the PLC- isozymes downstream of multiple receptor types. These studies will also advance our overall goal of a deeper, yet more parsimonious, understanding of signaling at biological membranes.