The high affinity Interleukin-15 receptor is a heterotrimer of Interleukin-15 receptor subunit alpha (IL15RA), Interleukin-2 receptor subunit beta (IL2RB, CD122) and Cytokine receptor common subunit gamma (IL2RG, CD132). IL2RB and IL2RG are also components of the Interleukin-2 (IL2) receptor. Treatment of human T cells with Interleukin-15 (IL15) results in tyrosine phosphorylation of Tyrosine-protein kinase JAK1 (JAK1, Janus kinase 1) and Tyrosine-protein kinase JAK3 (JAK3, Janus kinase 3) (Johnston et al. 1995, Winthrop 2017). IL15 can signal by a process termed 'trans presentation', where IL15 bound by IL15 on one cell is trans-presented to IL2RB:IL2RG on another cell (Dubois et al. 2002) but can also participate in more 'traditional' cis signaling (Wu et al. 2008, Mishra et al. 2014) where all the three receptors are present on the same cell.
Stimulation of lymphocytes by IL15 release MAPK activation through GAB2/SHP2/SHC (GRB2-associated-binding protein 2/Tyrosine-protein phosphatase non-receptor type 11/SHC transforming protein 1 or 2) cascade activation (Gadina et al. 2000).
Gadina M, Sudarshan C, Visconti R, Zhou YJ, Gu H, Neel BG, O'Shea JJ.; ''The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines.''; PubMedEurope PMCScholia
Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM.; ''Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor.''; PubMedEurope PMCScholia
Mishra A, Sullivan L, Caligiuri MA.; ''Molecular pathways: interleukin-15 signaling in health and in cancer.''; PubMedEurope PMCScholia
Winthrop KL.; ''The emerging safety profile of JAK inhibitors in rheumatic disease.''; PubMedEurope PMCScholia
Dubois S, Mariner J, Waldmann TA, Tagaya Y.; ''IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells.''; PubMedEurope PMCScholia
Wu L, Zepp JA, Qian W, Martin BN, Ouyang W, Yin W, Bunting KD, Aronica M, Erzurum S, Li X.; ''A novel IL-25 signaling pathway through STAT5.''; PubMedEurope PMCScholia
Floss DM, Klöcker T, Schröder J, Lamertz L, Mrotzek S, Strobl B, Hermanns H, Scheller J.; ''Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases.''; PubMedEurope PMCScholia
Anderson DM, Kumaki S, Ahdieh M, Bertles J, Tometsko M, Loomis A, Giri J, Copeland NG, Gilbert DJ, Jenkins NA.; ''Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes.''; PubMedEurope PMCScholia
Zambricki E, Shigeoka A, Kishimoto H, Sprent J, Burakoff S, Carpenter C, Milford E, McKay D.; ''Signaling T-cell survival and death by IL-2 and IL-15.''; PubMedEurope PMCScholia
Adunyah SE, Wheeler BJ, Cooper RS.; ''Evidence for the involvement of LCK and MAP kinase (ERK-1) in the signal transduction mechanism of interleukin-15.''; PubMedEurope PMCScholia
Giron-Michel J, Caignard A, Fogli M, Brouty-Boyé D, Briard D, van Dijk M, Meazza R, Ferrini S, Lebousse-Kerdilès C, Clay D, Bompais H, Chouaib S, Péault B, Azzarone B.; ''Differential STAT3, STAT5, and NF-kappaB activation in human hematopoietic progenitors by endogenous interleukin-15: implications in the expression of functional molecules.''; PubMedEurope PMCScholia
Waldmann TA, Tagaya Y.; ''The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens.''; PubMedEurope PMCScholia
Vignali DA, Kuchroo VK.; ''IL-12 family cytokines: immunological playmakers.''; PubMedEurope PMCScholia
Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD.; ''Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15.''; PubMedEurope PMCScholia
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The receptor chains are also utilized by multiple cytokines (Fig. 1)1,2. IL-12 signals via IL12Rβ1 and IL12Rβ248,71,72, while IL-23 signals through IL12Rβ1 and IL23R69,73. In contrast, IL-27 utilizes gp130 and WSX-174, while IL-35 signals via gp130 and IL12Rβ228. IL-35 is unusual in that it can also signals via two additional receptor chain compositions; gp130-gp130 and IL12Rβ2-lL12Rβ2 homodimers28. Signaling via all of these receptors is mediated by members of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) family27,75,76 (Fig. 1). JAK2 and either JAK1 or TYK2 appear to mediate phosphorylation of the IL-12 cytokine receptors family-associated STATs. IL-12 mediates signaling via pSTAT477, IL-23 via pSTAT3 and pSTAT469,73, IL-27 via pSTAT1 and pSTAT378,79, and IL-35 via pSTAT1 and pSTAT428. For IL-35, formation of a STAT1:STAT4 heterodimer is required for Ebi2/ Il12a transcription, but partially dispensable for supression28 (PMID:22814351)
Inferred from mouse:
Interleukin-25 (IL25 or IL17E) stimulation had any effect on the phosphorylation of STAT proteins. Although IL25 had no effect on the activation of Signal transducer and activator of transcription 6 (STAT6) and Signal transducer and activator of transcription 3 (STAT3), IL25 stimulation led to the activation of Signal transducer and activator of transcription 5A or 5B (STAT5), as indicated by the phosphorylation of STAT5 (Wu et al. 2015). This is a black box event since the details about of the phosphorylated region could be incomplete.
The Interleukin-15 (IL15) / Interleukin-15 receptor subunit alpha (IL15RA, IL15Rα) complex binds Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Cytokine receptor common subunit gamma (IL2RG, IL2Rγ), which is associated with Tyrosine-protein kinase JAK3 (JAK3) (Johnston et al. 1995). The heterodimer of IL2RB and IL2RG can bind IL15 with low affinity but high affinity binding requires a third component, IL15RA (Giri et al. 1994, 1995, Anderson et al. 1995). This is a Black Box Event because it is not clear whether the beta and gamma subunits pre-associate before binding IL15:IL15RA.
The Interleukin-15 (IL15) / Interleukin-15 receptor subunit alpha (IL15RA, IL15Rα) complex binds Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ), which is associated with Tyrosine-protein kinase JAK1 (JAK1) and Cytokine receptor common subunit gamma (IL2RG, IL2Rγ), which is associated with Tyrosine-protein kinase JAK3 (JAK3) (Johnston et al. 1995). The heterodimer of IL2RB and IL2RG can bind IL15 with low affinity but high affinity binding requires a third component, IL15RA (Giri et al. 1994, 1995, Anderson et al. 1995). This is a Black Box Event because it is not clear whether the β and γ subunits pre-associate before binding IL15:IL15RA.
Inferred from mouse: Coimmunoprecipitation studies show that SHC transforming protein 1 (SHC1) associates with Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ) as part of the Interleukin-2 (IL2) receptor complex (Gadina et al. 2000). Similar binding in IL15 receptor complex can be inferred from IL15 stimulates SHC1 phosphorylation (Zambricki et al. 2005). More in detail, human and mouse IL15 have 70.2% amino acid sequence similarity and exhibit similar trans-presentation mechanism, signal transduction machinery and biological activities. Similarly, human IL15 shows cross-reactivity with mouse cells and it was demonstrated that human and mouse IL15 showed similar responses in mouse models (Stoklasek et al. 2006) (Patidar et al. data not published). IL15 helps in B cell proliferation via two pathways: IL15–STAT5 and IL15–SHC–Ras–Raf–ERK pathway (Patidar et al. 2016).This is a black box event because there is no direct evidence of SHC1 binding after IL15 stimulation.
Tyrosine-protein kinase JAK1(JAK1) and Tyrosine-protein kinase JAK3 (JAK3) are believed to be phosphorylated after stimulation of the Interleukin-15 receptor complex by Interleukin-15 (IL15) (Johnston et al. 1995), though it has been reported that only JAK3 phosphorylation increases in response to IL15 (Krolopp et al. 2016). The Interleukin-15 receptor complex consists of IL15, Interleukin-15 receptor alpha subunit (IL15RA, IL15Rα), Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ), which is associated with JAK1 and Interleukin receptor gamma subunit, which is associated with JAK3 (Johnston et al. 1995). This is a black box event since the mechanism by which IL15 promotes JAK phosphorylation is unclear.
Interleukin 15 (IL15) binds Interleukin 15 receptor subunit alpha (IL15RA, IL15Rα). The high affinity Interleukin 15 receptor is a heterotrimer of IL15RA, Interleukin 2 receptor subunit beta (IL2RB, IL2Rβ, IL15RB) and Cytokine receptor common subunit gamma (IL2RG, IL2Rγ). IL15RA is structurally related to the alpha subunit of the Interleukin-2 receptor and determines high affinity binding for Interleukin 15 (IL15) (Giri et al. 1994, 1995, Anderson et al. 1995, Dubois et al. 2002). More in detail, IL15RA binds specifically to IL15 with high affinity (Kd=30-100 pM), whereas IL2RA specifically binds to IL2 with a comparatively lower affinity (Kd=10-30 nM) (Bernard et al. 2004).
Inferred from mouse: Interleukin-15 (IL15) stimulates the phosphorylation of SHC1 bound to Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ) (Zambricki et al 2005), which is a component of the IL15 and IL2 receptor complexes (Bennet et al. 1994, Li et al. 1994). More in detail, human and mouse IL15 have 70.2% amino acid sequence similarity and exhibit similar trans-presentation mechanism, signal transduction machinery and biological activities. Similarly, human IL15 shows cross reactivity with mouse cells and it was demonstrated that human and mouse IL15 showed similar responses in mouse models (Stoklasek et al. 2006) (Patidar et al. data not published).
The formation of Interleukin-15/Interleukin-15 receptor alpha complexes (IL15:IL15RA or IL15: IL15Rα) on cell surfaces induce a trans-endosomal recycling of IL15 leading to the persistence of surface-bound IL15 due to the constant reappearance of IL15 on plasma membranes. This complex contributes to the long survival of T cells expressing IL15RA after IL15 withdrawal (Dubois et al. 2000). This is a black box event since the details of other potential receptors and proteins participating in this event, remain unclear. It is shown similar patterns for other interleukins (i.e: Interleukin-12, Chiaruttini et al. 2016).
Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 5A or 5B (STAT5A,STAT5B or STAT5) are phosphorylated after Interleukin 15 (IL15) stimulation of the IL15 receptor complex (Johnston et al. 1995, Lin et al. 1995, Okada et al. 2015, Cooley et al. 2015, Krolopp et al. 2016), which consists of IL15, Interleukin-15 receptor subunit alpha (IL15RA, IL15Rα), Interleukin 2 receptor beta subunit (IL2RB, IL2Rβ), Tyrosine protein kinase JAK1 (JAK1), Cytokine receptor common subunit gamma (IL2RG, IL2Rγ) and Tyrosine protein kinase JAK3 (JAK3).<br>Treatment of human T cells with Interleukin 15 (IL15) and Interleukin 2 (IL2) resulted in the tyrosine phosphorylation of JAK1 and JAK3. Additionally, there was a rapid induction of DNA binding complexes that contained STAT3 and STAT5, both of which were tyrosine phosphorylated (Johnston et al. 1995).This is a black-box event because it is not clear which receptor-associated kinase is responsible for STAT phosphorylation.
Signal transducer and activator of transcription 3 (STAT3) is believed to bind Signal transducer and activator of transcription 5A/5B (STAT5). IL15 stimulation leads to the formation of DNA binding complexes that contain STAT3 and STAT5 (Johnston et al. 1995, Giron-Michel et al. 2003). This is a black box event because dimer formation is inferred from STAT3 and STAT5 co-occurrence in DNA binding complexes.
Phosphorylated Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 5A/5B (STAT5A and STAT5B, respectively, or STAT5) dissociate from the Interleukin-15 (IL15) receptor complex, which consists of IL15, Interleukin-15 receptor subunit alpha (IL15RA, IL15Rα), Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ), Tyrosine-protein kinase JAK1 (JAK1), Cytokine receptor common subunit gamma (IL2RG, IL2Rγ) and Tyrosine-protein kinase JAK3 (JAK3). Recombinant IL15 (10 ng/mL) induces the translocation of pSTAT3 to the nucleus (Giron Michel et al. 2003). In mast cells, IL15-stimulated STAT5 activation has been suggested to involve Tyrosine protein kinase JAK2 (JAK2) rather than JAK1/JAK3 signaling (Waldman & Tagaya 1999). More in detail, mast cells have unique receptors for IL15 i.e., IL15 Receptor X (IL15RX). Binding of IL15 with IL15 RX (Tagaya et al. 1996) on mast cells induces mast cell growth by activation of JAK2/STAT5 pathways and mast cell differentiation by Non-receptor tyrosine-protein kinase TYK2/Signal transducer and activator of transcription 6/Interleukin-4 pathway(TYK2/STAT6/IL4 pathway) (Jackson et al. 2005). This is black box event because dissociation is inferred from the identification of STAT3 and STAT5 in DNA binding complexes after IL15 stimulation (Johnston et al. 1995, Giron Michel et al. 2003).
Signal transducer and activator of transcription 3 (STAT3), Signal transducer and activator of transcription 5A and 5B (STAT5) are believed to bind the Interleukin-15 (IL15) receptor complex, which consists of IL15, Interleukin-15 receptor alpha subunit (IL15RA, IL15Rα), Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ), which is associated with JAK1 and Interleukin receptor gamma subunit, which is associated with JAK3 (Johnston et al. 1995). This is a black-box event because STAT binding is inferred from their subsequent phosphorylation.
Signal transducer and activator of transcription 3 (STAT3) and Signal transducer and activator of transcription 5A/5B (STAT5A and STAT5B respectively or STAT5) dimers translocate from the cytosol to the nucleoplasm. 10 ng/mL Interleukin-15 (IL15) induces the nuclear localization of phosphorylated STAT3, unless inhibited by neutralizing anti-IL15 or anti-Interleukin receptor alpha subunit (IL15RA, IL15Rα) mAbs (Giron Michel et al.2003, Johnston et al. 1995).This is a black box event because nuclear translocation of phosphorylated STAT3:STAT5 dimers has not been demonstrated but is inferred from other Jak-Stat signaling events.
Son of sevenless homolog 2 (SOS2) is believed to bind the Interleukin-15 (IL15) receptor complex (Mishra et al. 2014). This is inferred from the binding of GRB2 to Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ) in the IL15 receptor complex (Zambricki et al. 2005) and Interleukin-2 receptor complex (Zhu et al. 1994) and from events that follow SHC-GRB2 association in IL2 receptor signaling. The Interleukin-15 (IL15) receptor complex consists mainly of IL15, Interleukin-15 receptor alpha subunit (IL15RA, IL15Rα), Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ), which is associated with JAK1 and Interleukin receptor gamma subunit, which is associated with JAK3 (Johnston et al. 1995). In IL2 signaling, the resulting GRB2:SOS complex activates the Ras-Raf pathway (Zhu et al. 1994) and is believed to participate in similar events in IL15 signaling (Anduyah et al. 1997, Mishra et al. 2014). This is a black box event because SOS1 binding to GRB2 in response to IL15 has not been demonstrated.
Inferred from mouse:GRB2 is recruited by phosphorylated SHC1 in the IL15 receptor complex (Zambricki et al. 2005, Gadina et al. 2000), as it is in the Interleukin-2 receptor complex (Li et al. 1994, Bennett et al. 1994).More in detail, human and mouse IL15 have 70.2% amino acid sequence similarity and exhibit similar trans-presentation mechanism, signal transduction machinery and biological activities. Similarly, human IL15 shows cross-reactivity with mouse cells and it was demonstrated that human and mouse IL15 showed similar responses in mouse models (Stoklasek et al. 2006) (Patidar et al. data not published).
Inferred from mouse: GRB2 associated binding protein 2 (GAB2) is phosphorylated in response to Interleukin-2 (IL2) and Interleukin-15 (IL15) stimulation. Its phosphorylation is greatly diminished by mutation of the Y338 site in Interleukin-2 Receptor beta chain (IL2RB, IL2Rβ) that recruits SHC transforming protein 1 (SHC1) (Gadina et al. 2000, Wöhrle et al. 2009, Gesbert et al. 1998, Brockdorff et al. 2001). The core Interleukin-15 (IL15) receptor complex consists of IL15, Interleukin-15 receptor alpha subunit (IL15RA, IL15Rα), Interleukin-2 receptor beta subunit (IL2RB, IL2Rβ), which is associated with JAK1 and Interleukin-2 receptor gamma subunit (IL2RG, IL2Rγ), which is associated with JAK3 (Johnston et al. 1995). In this event, the IL15 receptor complex also includes phosphorylated SHC1, GRB2 and GAB2. This is a black box event because the kinase responsible for GAB2 phosphorylation has not been demonstrated.
Inferred from mouse: GRB2 associated binding protein 2 (GAB2) is believed to bind and be phosphorylated in response to Interleukin-2 (IL2) and Interleukin-15 (IL15) stimulation. Its phosphorylation is greatly diminished by mutation of the site in the Interleukin-2 Receptor beta chain (Y338F) (IL2RB, IL2Rβ) that recruits SHC transforming protein 1 (SHC1) (Gadina et al.2000, Wöhrle et al.2009, Gesbert et al. 1998, Brockdorff et al. 2001). GAB2 is a phosphoprotein that is suggested to associates with PI3kinase, Growth factor receptor-bound protein 2 (GRB2) and Tyrosine protein phosphatase non-receptor type 11 (PTPN11 or SHP2) in T and Natural Killer (NK) cells (Gu et al. 2000).This is a black box event because GAB2 binding is inferred from IL15 stimulation of GAB2 phosphorylation (Brockdorff et al. 2001). More in detail, human and mouse IL15 have 70.2% amino acid sequence similarity and exhibit similar trans-presentation mechanism, signal transduction machinery and biological activities. Similarly, human IL15 shows cross-reactivity with mouse cells and it was demonstrated that human and mouse IL15 showed similar responses in mouse models (Stoklasek et al. 2006) (Patidar et al. data not published).
Inferred from mouse: Interleukin-2 receptor subunit beta (IL2RB, IL2Rβ) and Cytokine receptor common subunit gamma (IL2RG, IL2Rγ) is tyrosine phosphorylated after Interleukin-15 (IL15) / IL15 receptor complex interaction (Adunyah et al. 1997, Zambricki et al. 2005). More in detail, human and mouse IL15 have 70.2% amino acid sequence similarity and exhibit similar trans-presentation mechanism, signal transduction machinery and biological activities. Similarly, human IL15 shows cross-reactivity with mouse cells and it was demonstrated that human and mouse IL15 showed similar responses in mouse models (Stoklasek et al. 2006) (Patidar et al. data not published). This is a black box event because more evidence to support this reaction is needed.
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Signaling via all of these receptors is mediated by members of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) family27,75,76 (Fig. 1). JAK2 and either JAK1 or TYK2 appear to mediate phosphorylation of the IL-12 cytokine receptors family-associated STATs. IL-12 mediates signaling via pSTAT477, IL-23 via pSTAT3 and pSTAT469,73, IL-27 via pSTAT1 and pSTAT378,79, and IL-35 via pSTAT1 and pSTAT428. For IL-35, formation of a STAT1:STAT4 heterodimer is required for Ebi2/ Il12a transcription, but partially dispensable for supression28 (PMID:22814351)
This is a black box event since the details about of the phosphorylated region could be incomplete.
Annotated Interactions