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-2Rbeta.
Interleukin-2 (IL-2) induces heterodimerization of the IL-2 receptor beta (IL-2Rbeta) and gammac chains of its receptor and activates the Janus family tyrosine kinases, Jak1 and Jak3. Whereas Jak1 associates with IL-2Rbeta, Jak3 associates primarily with gammac but also with IL-2Rbeta. We analyzed four IL-2Rbeta 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-2Rbeta membrane-proximal region, we investigated and found that each mutation diminished IL-2Rbeta association with both Jak1 and Jak3. This suggested that these Jaks might interact with the same region of IL-2Rbeta; however, certain IL-2Rbeta internal deletions and C-terminal truncations differentially affected the association of Jak1 and Jak3. Interestingly, just as Jak1-IL-2Rbeta association is Jak3-independent and functionally important, we show that Jak3-IL-2Rbeta 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-2Rbeta, suggesting that these kinases can simultaneously bind to IL-2Rbeta. 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-2Rbeta-Jak kinase interactions are important for IL-2 signaling.
Zhu
M H
MH
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
Berry
J A
JA
Russell
S M
SM
Leonard
W J
WJ
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D051379:Mice; D008894:Milk Proteins; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507933:JAK3 protein, human; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3