CHARACTERIZATION OF A MOBILE STAT6 ACTIVATION MOTIF IN THE HUMAN IL-4RECEPTOR

The IL-4R induces proliferation and gene expression through the use of conserved tyrosine residues located in growth and gene regulation dom ains, respectively. We demonstrate that residues surrounding these con served tyrosines (juxtatyrosine residues) are essential for the proper activation of the signaling molecules IRS-2 and Stat6, as well as for IL-4-induced gene expression. Further, we found that the IL-4R gene r egulation domain (amino acids 557-657) contains a tyrosine-based seque nce (EAGYKAF) that can convey Stat6 DNA binding and gene expression ac tivities to a minimally active IL-4R mutant, Delta 557. Thus, this tyr osine-based sequence can function as a mobile Stat6 activation cassett e. However, mutants bearing this sequence induced CD23 expression much less efficiently than did wild-type IL-4R, requiring 150-fold more IL -4 to reach maximal CD23 expression. Our results indicate the importan ce of juxtatyrosine residues in IL-4R signaling and argue for an essen tial role of extended domain structure in the recognition and function of juxtatyrosine sequences.