RETRACTED: A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control (Retracted Article. See vol 30, pg 627, 2011)

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