INTERLEUKIN-9 INDUCES TYROSINE PHOSPHORYLATION OF INSULIN-RECEPTOR SUBSTRATE-1 VIA JAK TYROSINE KINASES

Interleukin (IL)-9 stimulates the proliferation of a variety of hemato poietic lineages through its interaction with a receptor of the cytoki ne receptor superfamily. In the studies presented here, we have begun to characterize the downstream signaling pathways activated by IL-9. I n addition to the activation of JAK1 and JAK3 tyrosine kinases, IL-9, unlike most hematopoietic cytokines but similar to IL-4, induces the t yrosine phosphorylation of a 170-kDa protein that is related to the in sulin receptor substrate-1 (IRS-1). We further demonstrate for the fir st time that IRS-1 is not only associated with JAK1 but also tyrosine phosphorylated and functionally involved in IL-9 signaling in TS1 lymp hocytes transfected with the murine IRS-1 cDNA. Cotransfection studies and in vitro experiments directly demonstrate that JAK1, JAK2, or JAK 3 is capable of tyrosine phosphorylating IRS-1, suggesting a functiona l role for these kinases in vivo. Lastly, we demonstrate that IL-9 ind uces the tyrosine phosphorylation of Stat3 and in this regard differs from IL-4, which triggers tyrosine phosphorylation of Stat6. Taken tog ether, these results strongly suggest that IL-9 and IL-4 utilize commo n and unique signaling pathways via inducing the similar and distinct tyrosine-phosphorylated proteins.