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 led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells 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 homodimerization. To test this latter possibility, a chimeric receptor containing 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 alpha-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, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation 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 induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).
Reichel
M
M
Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Nelson
B H
BH
Greenberg
P D
PD
Rothman
P B
PB
D015703:Antigens, CD / Q000032:analysis*; D001483:Base Sequence; D002478:Cells, Cultured; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D015847:Interleukin-4; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D018123:Receptors, Interleukin / Q000032:analysis*; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D015703:Antigens, CD; D018123:Receptors, Interleukin; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C507904:JAK1 protein, human; C507933:JAK3 protein, human; D053613:Janus Kinase 1; D053616:Janus Kinase 3