Specific low-affinity receptors for leukemia inhibitory factor (LIF), oncostatin M (OSM; gp130), and ciliary neurotrophic factor (CNTF; receptor alpha, CNTFRalpha) may be utilized in various combinations to generate high-affinity binding sites and signal transduction. We have tested the ability of combinations of these receptors to transduce a proliferative signal in BAF-B03 cells. Coexpression of the LIF receptor and gp130 in these cells conferred high-affinity LIF and OSM binding and responsiveness to LIF and OSM. These cells also responded to CNTF in the absence of detectable binding. The further addition of CNTFRalpha conferred high-affinity CNTF binding and enhanced responsiveness to CNTF but did not modify responses to LIF or OSM. Coexpression of LIF receptor and CNTFRalpha resulted in a nonfunctional high-affinity binding site. These data are consistent with a role for the CNTFRalpha in enhancing CNTF action but the CNTFRalpha is not absolutely required for CNTF action and suggest a wider range of targets for CNTF.