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  • The EMBO Journal (2005) 24, 4260 - 4270
  • doi:10.1038/sj.emboj.7600874

Published online: 24 November 2005

A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control

Vadim Budagian1, Elena Bulanova1, Zane Orinska1, Lutz Thon2, Uwe Mamat1, Paola Bellosta3, Claudio Basilico4, Dieter Adam2, Ralf Paus5 and Silvia Bulfone-Paus1

  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

Correspondence to:

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

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.

  • Keywords:

    • fibroblast,
    • Gas6,
    • TNFalpha,
    • transactivation