Mechanisms and Manifestations of Ligand Bias in Signaling: Focus on Receptor Tyrosine Kinases

The development of organisms and the maintenance of tissue homeostasis depend on complex intercellular signaling networks that govern basic cell functions. Because cells are typically exposed to many diverse ligands simultaneously, distinct intracellular mechanisms of cell signaling have evolved, allowing cells to accurately sense and respond to their environment. Here, we discuss the concept of ligand bias, which describes the ability of different ligands to preferentially activate specific signaling pathways, and thus produce divergent responses through the same receptor. Although bias can be challenging to identify and quantify, protocols have been established to (i) determine whether preferences exist and (ii) quantify these preferences. We review these protocols and their utility in studies of signaling by RTKs, the largest family of single-pass membrane receptors. We summarize the literature suggesting that RTKs engage in biased signaling and discuss the utility of signaling bias in therapeutics design. We discuss parallels with GPCR biased signaling, and lessons that have been learned after years of GPCR signaling research. Finally, we propose that RTK ligand bias appeared in evolution to diversify the morphogen signaling pathways that direct the development of tissues and organs in the mammalian body.