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

Vadim Budagian1, Elena Bulanova, Zane Orinska

  • 1Department of Immunology & Cell Biology, Research Center Borstel, Borstel, Germany.

The EMBO Journal
|November 26, 2005
PubMed

Insights

Interleukin-15 (IL-15) signaling involves a novel complex with the tyrosine kinase Axl, revealing a cross-talk between cytokine and receptor tyrosine kinase pathways. This interaction is crucial for protecting cells from tumor necrosis factor alpha (TNFalpha)-induced death.

Area of Science:

  • Cellular signaling
  • Immunology
  • Molecular biology

Background:

  • Cytokine receptor and receptor tyrosine kinase (RTK) pathways are distinct signaling paradigms.
  • Interleukin-15 (IL-15) mediates cellular responses, including protection from cell death.
  • Tumor necrosis factor alpha (TNFalpha) induces cell death in various cell types.

Purpose of the Study:

  • To investigate the interaction between IL-15 signaling and RTK pathways.
  • To elucidate the role of the RTK Axl in IL-15-mediated protection from TNFalpha-induced cell death.
  • To identify novel components of the IL-15 receptor complex.

Main Methods:

  • Utilized murine L929 fibroblasts with targeted depletion and overexpression of Axl.
  • Performed co-localization and co-immunoprecipitation assays to study receptor interactions.
  • Investigated tyrosine phosphorylation and downstream signaling pathways (PI3K/Akt) upon IL-15 stimulation.
  • Examined responses in embryonic fibroblasts from wild-type, Axl-/-, and IL-15Ralpha-/- mice.

Main Results:

  • IL-15 protects L929 fibroblasts from TNFalpha-induced death, dependent on the presence of Axl.
  • IL-15 receptor alpha (IL-15Ralpha) and Axl colocalize and interact on the cell membrane, requiring Axl's extracellular domain.
  • IL-15 stimulation leads to tyrosine phosphorylation of both Axl and IL-15Ralpha, activating the PI3K/Akt pathway.
  • This cross-activation is observed in wild-type but not in Axl-/- or IL-15Ralpha-/- fibroblasts.

Conclusions:

  • A novel IL-15 receptor complex exists, comprising IL-15Ralpha and Axl RTK.
  • IL-15 transactivates Axl signaling, integrating cytokine and RTK pathways.
  • This cross-talk is essential for IL-15-mediated protection against TNFalpha-induced apoptosis.

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