Interleukin-4 induces association of the c-fes proto-oncogene product with phosphatidylinositol-3 kinase

We have previously demonstrated that interleukin-4 (IL-4) induces tyrosine phosphorylation of a protein closely related or identical to the c-fes proto-oncogene product (FES) and association of this protein with the IL-4 receptor a chain (IL-4R alpha). IL-4 is known to induce association of phosphatidylinositol-3 (P13) kinase with the IL-4R alpha. Since FES contains the consensus motifs for P13 kinase binding, we tested the possibility that FES may associate with P13 kinase upon IL-4 stimulation. We demonstrate herein that IL-4 stimulation induced rapid association of FES or a related protein with P13 kinase in mouse T-cell lines. We also show an association of human FES (hFES) with the src homology 2 (SH2) domain of P13 kinase in a COS7 cell expression system. The in vitro P13 kinase assay using COS7 cells suggested that hFES partly contributes to the association between the hlL-4R alpha and P13 kinase. We have further identified the important region in the cytoplasmic domain of the hlL-4R alpha for association of tyrosine-phosphorylated hFES with the hlL-4R alpha and SH2 domain of P13 kinase using a COS7 cell expression system. These results suggest that FES or a related protein/P13 kinase pathway may play a role in the pleiotropic effects of IL-4. (C) 1996 by The American Society of Hematology.