The binding of a ligand to a cell-surface receptor represents a first step in transmitting extracellular information to the cell in order to activate downstream intracellular signaling events. This report describes the de novo engineering of cells with a transmembrane signal transduction motif that is developed from first principles. The signaling event is initiated with a polyvalent ligand that clusters an engineered receptor in the membrane. The receptor presents a cytosolic kinase substrate that undergoes autocatalytic phosphorylation when organized in a cluster, but not in the unclustered arrangement. The example described here may represent a motif that can be used in synthetic biology for the engineering of cells with novel circuits.