THE IL-4 RECEPTOR ALPHA-CHAIN CYTOPLASMIC DOMAIN IS SUFFICIENT FOR ACTIVATION OF JAK-1 AND STAT6 AND THE INDUCTION OF IL-4-SPECIFIC GENE-EXPRESSION

The common gamma-chain (gamma(c)) is a functional component of the IL- 4R, yet cells lacking gamma(c) are able to respond to IL-4. This has l ed to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cell s lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by hom odimerization. To test this latter possibility, a chimeric receptor co ntaining the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alph a-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells, SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, includin g up-regulation of CD23 and synthesis of germ-line epsilon transcripts . In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellul ar proliferation, Finally, in JAK-1-deficient HeLa cells, STAT6 activa tion by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK -1 and STAT6 and to induct expression of IL-4 target genes, thus ident ifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).