Selection of multiple agonist antibodies from intracellular combinatorial libraries reveals that cellular receptors are functionally pleiotropic

•Orthogonal agonists such as antibodies for a given receptor can induce cell fates different than the natural ligand.•As examples, an antibody agonist that activates DDR1 induces osteoclasts from bone marrow stem cells whereas those against UNC5C or the G-CSF receptor induce bone marrow stem cells to become neural cells.•The phenomenon of functional receptor pleiotropism greatly expands signal transduction potential of cells.•Increasing the signal transduction potential allows one greater control over cell fates.

The main purpose of this perspective is to build on the unexpected outcomes of previous laboratory experiments using antibody agonists to raise questions concerning how activation of a given receptor can be involved in inducing differentiation of cells along different pathways some of which may even derive from different lineages. While not yet answered, the question illustrates how the advent of agonists not present in nature may give a different dimension to the important problem of signal transduction. Thus, if one studies a natural agonist–receptor system one can learn details about its signal transduction pathway. However, if one has a set of orthogonal agonists, one may learn about the yet undiscovered potential of the system that, in the end, may necessitate refinements to the currently used models. Thus, we wonder why receptors conventionally linked to a given pathway induce a different pattern of differentiation when agonized in another way.