page_title: Interleukin 15
section_title: Signaling
hierarchical_section_title: Interleukin 15 / Signaling
caption_attribution_description: Čeština: Signalizace IL-15
context_page_description: Interleukin-15 is a cytokine with structural similarity to Interleukin-2. Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus. This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.
context_section_description: The prevailing mechanism of IL-15 action seems to be juxtacrine signaling or also determined as cell-to-cell contact. It also includes intracrine and reverse signaling. IL-15 was initially characterized as a soluble molecule. Later it was shown that IL-15 also exists as a membrane-bound form which represents the major form of IL-15 protein. In membrane-bound form it could be bound directly to cellular membrane or presented by IL-15Rα receptor.
  The main mechanism of IL-15 signaling is trans-presentation which is mediated by membrane-bound complex IL-15/IL-15Rα (Figure 3). IL-15 bind to IL-15Rα receptor alone with affinity (Kₐ = 1.10¹¹/M). It can also bind to IL-15Rβγc signaling complex with lower affinity (Kₐ = 1.10⁹/M) (Figure 4).
  Signaling pathway of IL-15 begins with binding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface. Upon binding IL-15β subunit activates Janus kinase 1 (Jak1) and γc subunit Janus kinase 3 (Jak3), which leads to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) and STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these cytokines have similar downstream effects including the induction of Bcl-2, MAP (mitogen-activated protein kinase) kinase pathway and the phosphorylation of Lck (lymphocyte-activated protein tyrosine kinase) and Syk (spleen tyrosine kinase) kinases, which leads to cell proliferation and maturation (Figure 5).
  In mast cells, the IL-15R signaling pathway has been found to include Jak2 and STAT5 instead Jak1/3 and STAT3/5. Phosphorylation STATs form transcription factors and activate transcription of appropriate genes. The β chain of IL-15R recruits and also activates protein tyrosine kinases of the Src family including Lck, Fyn and Lyn kinase. It also activates phosphatidylinositol 3-kinase (PI3K) and AKT signaling pathway and induce expression of transcription factors including c-Fos, c-Jun, c-Myc and NF-κB.
  IL-15 is also able to bind to the 15Rβγc signaling complex with intermediate affinity without requirement for IL-15Rα receptor. Upon binding IL-15 to signaling complex,  kinases of the Src family including Lck and Fyn are activated, and subsequently activates PI3K and MAPK signaling pathway. The second mechanism of IL-15 action is cis-presentation, when IL-15 is presented by IL-15Rα to 15Rβγc signaling complex on the same cell. This mechanism is mediated by the C-terminus flexibility which is mediated by 32 amino acids linker and/or 74 amino acids long PT region (Figure 6).
caption: Figure 5.  Signaling pathway of IL-15 begins with binding to IL-15Rα receptor, with subsequent presentation to surrounding cells bearing IL-15Rβγc complex on their cell surface. Upon binding IL-15β subunit activates Janus kinase 1 (Jak1) and γc subunit Janus kinase 3 (Jak3), which leads to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3) and STAT5. Due to sharing of receptor subunits between IL-2 and IL-15, both of these cytokines have similar downstream effects including the induction of B-cell lymphoma (Bcl-2), MAP (mitogen-activated protein kinase) kinase pathway and the phosphorylation of Lck (lymphocyte-activated protein tyrosine kinase) and Syk (spleen tyrosine kinase) kinases, which leads to cell proliferation and maturation.
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