Cells have various receptors on their surface for responding to extracellular signals that involve intercellular communication. Although the mechanism of signal transduction by such wild-type receptors has been studied intensively, there has been minimal effort in investigating whether such receptors could signal when unnaturally coupled. In this study, we investigated whether unnatural receptor pairs comprising interleukin-2 (IL-2) and interleukin-6 (IL-6) receptor subunits could transduce a signal through forced dimerization. We replaced the extracellular domain of IL-2R and IL-6R signaling subunits (IL-2R, IL-2R, and gp130) with the FK506-binding protein (FKBP) or the FKBP12-rapamycin binding (FRB) domain, the protein pair known to be heterodimerized by rapamycin. When expressed in a hematopoietic cell line, unnatural heterodimers (IL-2R-gp130 and IL-2R-gp130 pairs) successfully transduced a signal. While the IL-2R-gp130 pair maximally mimicked gp130 signaling, the IL-2R-gp130 pair gave weaker gp130 signaling and no significant induction of IL-2R signaling, indicating a high potential of the IL-2R chain in terms of activating the coupled partners. This is the first report demonstrating that heterodimeric combinations of IL-2R and IL-6R subunits are functional for signaling. Further extension of this approach may attain a creative design of artificial receptor pairs that have distinct signaling properties when compared with natural receptors. (c) 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1512-1518, 2013