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| Subject Categories: Signal Transduction | Differentiation & Death |
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| The EMBO Journal
(2005) 24, 4260–4270, doi:10.1038/sj.emboj.7600874 Published online 24 November 2005 |
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| A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control |
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| Vadim Budagian1, Elena Bulanova1, Zane Orinska1, Lutz Thon2, Uwe Mamat1, Paola Bellosta3, Claudio Basilico4, Dieter Adam2, Ralf Paus5 and Silvia Bulfone-Paus1 |
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1 Research Center Borstel, Borstel, Germany 2 Institute of Immunology, University of Kiel, Kiel, Germany 3 Department of Medical Sciences, Novara, Italy 4 Department of Microbiology, School of Medicine, New York, NY, USA 5 Department of Dermatology, University of Lübeck, Lübeck, Germany To whom correspondence should be addressed Silvia Bulfone-Paus, Department of Immunology & Cell Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany. Tel.: +49 4537 188200; Fax: +49 4537 188403; E-mail: sbulfone@fz-borstel.de Received 9 May 2005; Accepted 24 October 2005; Published online 24 November 2005. |
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| Abstract |
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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  (TNF)-induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl-overexpressing fibroblasts are TNF-resistant. IL-15R 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 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, 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-/- mice. Thus, IL-15-induced protection from TNF-mediated cell death involves a hitherto unknown IL-15 receptor complex, consisting of IL-15R and Axl RTK, and requires their reciprocal activation initiated by ligand-induced IL-15R. |
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| Keywords: fibroblast, Gas6, TNF, transactivation |
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