Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes.
Interleukins-2 and -15 (IL-2 and IL-15) are cytokines with overlapping but distinct biological effects. Their receptors share two subunits (the IL-2R beta and -gamma chains) that are essential for signal transduction. The IL-2 receptor requires an additional IL-2-specific alpha subunit for high affinity IL-2 binding. Recently, a murine IL-15-specific alpha subunit was identified, cloned, and shown to be structurally related to IL-2R alpha. However, the murine IL-15R alpha alone bound IL-15 with a 1000-fold higher affinity than that seen with IL-2R alpha and IL-2. We now extend these studies into the human system with the isolation of three differentially spliced human IL-15R alpha variants that are all capable of high affinity binding of IL-15. The cytoplasmic domain of IL-15R alpha, like that of IL-2R alpha, is dispensable for mitogenic signaling, suggesting that the primary role of the alpha chains is to confer high affinity binding. At high concentrations, IL-15, like IL-2, is able to signal through a complex of IL-2R beta and -gamma in the absence of the alpha subunit. Furthermore, the IL15RA and IL2RA genes have a similar intron-exon organization and are closely linked in both human and murine genomes. However, the distribution of expression of the IL-15R alpha is much wider than that of the IL-2R alpha, suggesting a broader range of cellular targets for IL-15.
Department of Molecular Biology, Immunex Corporation, Seattle, Washington 98101, USA.
D M
DM
Anderson
S
S
Kumaki
M
M
Ahdieh
J
J
Bertles
M
M
Tometsko
A
A
Loomis
J
J
Giri
N G
NG
Copeland
D J
DJ
Gilbert
N A
NA
Jenkins
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D017931:DNA Primers; D005260:Female; D008040:Genetic Linkage; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019409:Interleukin-15; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016133:Polymerase Chain Reaction; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics*; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured
D017931:DNA Primers; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D007378:Interleukins; D046911:Macromolecular Substances; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2