To examine the region critical for differentiation in the human IL-4 receptor (hIL-4R), we transfected the Abelson murine leukemia virus (A-MuLV)-transformed murine pre-B cell line A20 with plasmid DNA encoding the hIL-4R. Transfectants expressed high affinity hIL-4Rs on the cell surface. Treatment with LPS and hIL-4 induced germline C epsilon transcripts in hIL-4R expressing A20 cells. Several hIL-4R mutant plasmids were then transfected into A20 cells and the transfectants were examined for hIL-4R expression and the ability to induce germline C epsilon transcripts upon stimulation with LPS and hIL-4. Although all A20 transfectants tested expressed the high-affinity hIL-4R, A20 transfectants expressing the mutant hIL-4R, which contains only 8 amino acids in the cytoplasmic domain, did not respond to LPS and hIL-4 with germline C epsilon transcripts. In addition, A20 transfectants expressing an internally deleted hIL-4R, in which the deleted region has been identified as the critical region for growth signal transduction in the previous study, failed to induce germline C epsilon transcripts with LPS and hIL-4. These results indicate that the critical region for the differentiation signal in the hIL-4R is identical to that for the growth signal, suggesting that IL-4 may share, at least partly, a common signal pathway for both growth and differentiation.