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

Vadim Budagian, Elena Bulanova, Zane Orinska, Lutz Thon, Uwe Mamat, Paola Bellosta, Claudio Basilico, Dieter Adam, Ralf Paus, Silvia Bulfone-Paus

Research output: Contribution to journalArticle

55 Scopus citations

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 en-ables 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.

Original languageEnglish (US)
Pages (from-to)4260-4270
Number of pages11
JournalEMBO Journal
Volume24
Issue number24
DOIs
StatePublished - Dec 21 2005
Externally publishedYes

Keywords

  • Fibroblast
  • Gas6
  • TNFα
  • Transactivation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Budagian, V., Bulanova, E., Orinska, Z., Thon, L., Mamat, U., Bellosta, P., Basilico, C., Adam, D., Paus, R., & Bulfone-Paus, S. (2005). A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control. EMBO Journal, 24(24), 4260-4270. https://doi.org/10.1038/sj.emboj.7600874