The IL-15R alpha chain signals through association with Syk in human B cells.
The alpha-chain of the IL-15R (IL-15Ralpha) serves as the specific, high-affinity receptor for IL-15. It is expressed by lymphoid and nonlymphoid cells, including B cell lymphoma lines. In this study, we have further explored IL-15Ralpha-mediated signaling in activated primary B cells and in Raji cells, a human B-lymphoblastoid cell line which expresses the IL-15Ralpha and IL-2Rgamma chains, but lacks the IL-2Rbeta chain. Stimulation of Raji cells with IL-15 induces their proliferation and rescues them from C2-ceramide-induced apoptosis. By immunoprecipitation and Western blotting, we show that treatment of Raji cells and activated primary B cells with IL-15 induces coprecipitation of Syk kinase with the IL-15Ralpha chain. Upon association, the activated Syk kinase phosphorylates the IL-15Ralpha chain as well as phospholipase Cgamma, which coprecipitates with Syk. Furthermore, transfection of Raji cells with stem-loop Syk antisense oligonucleotides prevents IL-15Ralpha and phospholipase Cgamma phosphorylation as well as the inhibition of apoptosis by IL-15. Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells.
Bulanova
E
E
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
Budagian
V
V
Pohl
T
T
Krause
H
H
Dürkop
H
H
Paus
R
R
Bulfone-Paus
S
S
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D020014:K562 Cells; D008213:Lymphocyte Activation; D016297:Mutagenesis, Site-Directed; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018909:src Homology Domains / Q000276:immunology
D004792:Enzyme Precursors; C508024:IL15RA protein, human; D019409:Interleukin-15; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C064769:N-acetylsphingosine; D016376:Oligonucleotides, Antisense; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D013110:Sphingosine; D002118:Calcium