A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control.
Discrimination between cytokine receptor and receptor tyrosine kinase (RTK) signaling pathways is a central paradigm in signal transduction research. Here, we report a 'promiscuous liaison' between both receptors that enables interleukin (IL)-15 to transactivate the signaling pathway of a tyrosine kinase. IL-15 protects murine L929 fibroblasts from tumor necrosis factor alpha (TNFalpha)-induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl-overexpressing fibroblasts are TNFalpha-resistant. IL-15Ralpha and Axl colocalize on the cell membrane and co-immunoprecipitate even in the absence of IL-15, whereby the extracellular part of Axl proved to be essential for Axl/IL-15Ralpha interaction. Most strikingly, IL-15 treatment mimics stimulation by the Axl ligand, Gas6, resulting in a rapid tyrosine phosphorylation of both Axl and IL-15Ralpha, and activation of the phosphatidylinositol 3-kinase/Akt pathway. This is also seen in mouse embryonic fibroblasts from wild-type but not Axl-/- or IL-15Ralpha-/- mice. Thus, IL-15-induced protection from TNFalpha-mediated cell death involves a hitherto unknown IL-15 receptor complex, consisting of IL-15Ralpha and Axl RTK, and requires their reciprocal activation initiated by ligand-induced IL-15Ralpha.
Budagian
Vadim
V
Department of Immunology & Cell Biology, Research Center Borstel, Borstel, Germany.
Bulanova
Elena
E
Orinska
Zane
Z
Thon
Lutz
L
Mamat
Uwe
U
Bellosta
Paola
P
Basilico
Claudio
C
Adam
Dieter
D
Paus
Ralf
R
Bulfone-Paus
Silvia
S
D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D002469:Cell Separation; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D002518:Ceramides; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D019409:Interleukin-15; D008024:Ligands; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse