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 α (TNFα)‐induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl‐overexpressing fibroblasts are TNFα‐resistant. IL‐15Rα 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‐15Rα interaction. Most strikingly, IL‐15 treatment mimics stimulation by the Axl ligand, Gas6, resulting in a rapid tyrosine phosphorylation of both Axl and IL‐15Rα, 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‐15Rα−/− mice. Thus, IL‐15‐induced protection from TNFα‐mediated cell death involves a hitherto unknown IL‐15 receptor complex, consisting of IL‐15Rα and Axl RTK, and requires their reciprocal activation initiated by ligand‐induced IL‐15Rα.