The IL-4R alpha contains the I4R motif which binds to the phosphotyrosine binding domain of several adaptor proteins, including IRS-1/2 and Shc. Although the involvement of IRS-1/2 in IL-Li-induced PI3-kinase activation is known, there is little information on the role of Shc in IL-4 signaling. In this study, we found the preferential utilization of Shc by the IL-4R alpha in a human Burkitt's B lymphoma cell line, DND39. IL-4 induced the association of tyrosine-phosphorylated Shc with the IL-4R alpha, whereas no detectable tyrosine phosphorylation of IRS-1 or IRS-S was induced, IL-4-induced germline epsilon promoter activation was enhanced by overexpression of Shc and was inhibited by truncated Shc lacking the collagen-homologous domain. mr, further found the association of Shc with PLC gamma 1. Although direct tyrosine phosphorylation of PLC gamma 1 was not detectable, the amount of PLC gamma 1 coprecipitable with anti-phosphotyrosine was increased after IL-4 stimulation. These results suggest that Shc can function as an adaptor protein of the IL-4R alpha and mediate the germline epsilon transcription.