Interleukin-2 (IL-2)-mediated induction of the IL-2 receptor alpha chain gene. Critical role of two functionally redundant tyrosine residues in the IL-2 receptor beta chain cytoplasmic domain and suggestion that these residues mediate more than Stat5 activation.
The interleukin-2 receptor alpha chain (IL-2Ralpha) is potently induced by antigens, mitogens, and certain cytokines that include IL-2 itself. This induction leads to the formation of high affinity IL-2 receptors when IL-2Ralpha is co-expressed with the beta (IL-2Rbeta) and gamma (gammac) chains of this receptor. We investigated the signaling pathways mediating IL-2-induced IL-2Ralpha mRNA expression using 32D myeloid progenitor cells stably transfected with either wild type IL-2Rbeta or mutants of IL-2Rbeta containing tyrosine to phenylalanine substitutions. Of the six cytoplasmic tyrosines in IL-2Rbeta, we have found that only the two tyrosines that mediate Stat5 activation (Tyr-392 and Tyr-510) contribute to IL-2-induced IL-2Ralpha gene expression and that either tyrosine alone is sufficient for this process. Interestingly, the IL-7 receptor contains a tyrosine (Tyr-429)-based sequence resembling the motifs encompassing Tyr-392 and Tyr-510 of IL-2Rbeta. Further paralleling the IL-2 system, IL-7 could activate Stat5 and drive expression of IL-2Ralpha mRNA in 32D cells transfected with the human IL-7R. However, IL-3 could not induce IL-2Ralpha mRNA in 32D cells, despite its ability to activate Stat5 via the endogenous IL-3 receptor. Moreover, the combination of IL-3 and IL-2 could not "rescue" IL-2Ralpha mRNA expression in cells containing an IL-2Rbeta mutant with phenylalanine substitutions at Tyr-392 and Tyr-510. These data suggest that Tyr-392 and Tyr-510 couple to an additional signaling pathway beyond STAT protein activation in IL-2-mediated induction of the IL-2Ralpha gene.
Ascherman
D P
DP
Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1674, USA.
Migone
T S
TS
Friedmann
M C
MC
Leonard
W J
WJ
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008894:Milk Proteins; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics*; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007377:Interleukin-3; D015851:Interleukin-7; D008894:Milk Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine