DELINEATION OF THE REGIONS OF INTERLEUKIN-2 (IL-2) RECEPTOR-BETA CHAIN IMPORTANT FOR ASSOCIATION OF JAK1 AND JAK3 - JAK1-INDEPENDENT FUNCTIONAL RECRUITMENT OF JAK3 TO IL-2R-BETA

Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor b eta (IL-2R beta) and gamma(c) chains of its receptor and activates the Janus family tyrosine kinases, Jak1 and Jak3, Whereas Jak1 associates with IL-2R beta, Jak3 associates primarily with gamma(c) but also wit h IL-2R beta. We analyzed four IL-2R beta mutations that diminish IL-2 -induced proliferation and found that each also decreased IL-2-induced signal transducer and activator of transcription (STAT) activation. F or this reason, and because the mutations were in the IL-2R beta membr ane-proximal region, we investigated and found that each mutation dimi nished IL-2R beta association with both Jak1 and Jak3. This suggested that these Jaks might interact with the same region of IL-2R beta; how ever, certain IL-2R beta internal deletions and C-terminal truncations differentially affected the association of Jak1 and Jak3, Interesting ly, just as Jak1-IL-2R beta association is Jak3-independent and functi onally important, we show that Jak3-IL-2R beta association is Jak1-ind ependent and implicate this association as being important for IL-2-in duced Stat5 activation. Moreover, Jak1 and Jak3 could associate only i n the presence of IL-2R beta, suggesting that these kinases can simult aneously bind to IL-2R beta, Thus, our data not only demonstrate that somewhat more distal as well as membrane-proximal cytoplasmic regions of a type I cytokine receptor are important for Jak kinase association but also suggest that two IL-2R beta-Jak kinase interactions are impo rtant for IL-2 signaling.