Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Animals
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Axl Receptor Tyrosine Kinase
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Cell Death
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Cell Differentiation
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Cell Line
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Cell Separation
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Ceramides / metabolism
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Cytokines / metabolism
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Dendritic Cells / cytology
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Enzyme Activation
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Enzyme-Linked Immunosorbent Assay
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Fibroblasts / metabolism
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Flow Cytometry
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Humans
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Intercellular Signaling Peptides and Proteins / metabolism
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Interleukin-15 / metabolism
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Interleukin-15 / physiology*
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Ligands
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Mice
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Mice, Transgenic
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Microscopy, Confocal
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Models, Biological
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Oncogene Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Binding
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Proto-Oncogene Proteins
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RNA, Small Interfering / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Interleukin-15
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Receptors, Interleukin-2 / chemistry
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Receptors, Interleukin-2 / metabolism*
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Recombinant Fusion Proteins / chemistry
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Transcriptional Activation
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Transfection
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Ceramides
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Cytokines
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IL15RA protein, human
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Il15ra protein, mouse
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Intercellular Signaling Peptides and Proteins
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Interleukin-15
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Ligands
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Oncogene Proteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Receptors, Interleukin-15
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Receptors, Interleukin-2
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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growth arrest-specific protein 6
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Phosphatidylinositol 3-Kinases
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Receptor Protein-Tyrosine Kinases
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Axl Receptor Tyrosine Kinase