Delineation of the regions of interleukin-2 (IL-2) receptor β chain important for association of Jak1 and Jak3 -: Jak1-independent functional recruitment of Jak3 to IL-2Rβ

Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor beta (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 with 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. For this reason, and because the mutations were in the IL-2R beta membrane-proximal region, we investigated and found that each mutation diminished IL-2R beta association with both Jak1 and Jak3. This suggested that these Jaks might interact with the same region of IL-2R beta; however, certain IL-2R beta internal deletions and C-terminal truncations differentially affected the association of Jak1 and Jak3, Interestingly, just as Jak1-IL-2R beta association is Jak3-independent and functionally important, we show that Jak3-IL-2R beta association is Jak1-independent and implicate this association as being important for IL-2-induced Stat5 activation. Moreover, Jak1 and Jak3 could associate only in the presence of IL-2R beta, suggesting that these kinases can simultaneously 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 important for IL-2 signaling.