Effects of cross-talk and pleiotropy on the specificity and accuracy of receptor signaling

Living cells and cell collectives crucially depend on the ability to sense their environment through engagement of external molecular signals with cell surface receptors. Puzzlingly, vast numbers of signaling pathways exhibit a high degree of cross-talk between different signals whereby different ligands act through the same receptor or shared components downstream. It remains unclear how a cell can accurately process information from the environment in such cross-wired pathways. We show that a feature which commonly accompanies cross-talk - receptor pleiotropy (the ability of the receptor to produce multiple outputs) - offers a solution to the cross-talk problem. In a minimal model of pleiotropic receptor cross-talk, we show that a single pleiotropic receptor is sufficient to simultaneously identify the ligand and accurately sense the concentration of a presented ligand, enabling specific and accurate signaling. We calculate the fundamental limits of the signaling specificity and accuracy of a pleiotropic receptor arising from the molecular noise both at the receptor level and downstream. We further investigate the effects of common signaling schemes such as Kinetic Proofreading (KPR) and show that KPR does not necessarily increase the signaling specificity once the effects of molecular noise are taken into account. The model serves as an elementary "building block" towards understanding more complex cross-wired receptor-ligand signaling networks, and suggests how cross-talk and pleiotropy might be inherent features of combinatorial signaling in cross-wired networks. The results of the paper suggest a novel outlook at a number of experimental systems.