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Human Interaction Network Ontology
| Preferred Name | Interleukin-2 signaling | |
| Synonyms |
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| Definitions |
Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.<br><br>IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c). The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells. |
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| ID |
http://purl.obolibrary.org/obo/HINO_0022232 |
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| comment |
Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2010-08-06 Interleukin-2 (IL-2) is a cytokine that is produced by T cells in response to antigen stimulation. Originally, IL-2 was discovered because of its potent growth factor activity on activated T cells in vitro and was therefore named 'T cell growth factor' (TCGF). However, the generation of IL-2- and IL-2 receptor-deficient mice revealed that IL-2 also plays a regulatory role in the immune system by suppressing autoimmune responses. Two main mechanisms have been identified that explain this suppressive function: (1) IL-2 sensitizes activated T cells for activation-induced cell death (AICD) and (2) IL-2 is critical for the survival and function of regulatory T cells (Tregs), which possess potent immunosuppressive properties.<br><br>IL-2 signaling occurs when IL-2 binds to the heterotrimeric high-affinity IL-2 receptor (IL-2R), which consists of alpha, beta and gamma chains. The IL-2R was identified in 1981 via radiolabeled ligand binding (Robb et al. 1981). The IL-2R alpha chain was identified in 1982 (Leonard et al.), the beta chain in 1986/7 (Sharon et al. 1986, Teshigawara et al. 1987) and the IL-2R gamma chain in 1992 (Takeshita et al.). The high affinity of IL-2 binding to the IL-2R is created by a very rapid association rate to the IL-2R alpha chain, combined with a much slower dissociation rate contributed by the combination of the IL-2R beta and gamma chains (Wang & Smith 1987). After antigen stimulation, T cells upregulate the high-affinity IL-2R alpha chain; IL-2R alpha captures IL-2 and this complex then associates with the constitutively expressed IL-2R beta and gamma chains. The IL-2R gamma chain is shared by several other members of the cytokine receptor superfamily including IL-4, IL-7, IL-9, IL-15 and IL-21 receptors, and consequently is often referred to as the Common gamma chain (Gamma-c).
The tyrosine kinases Jak1 and Jak3, which are constitutively associated with IL-2R beta and Gamma-c respectively, are activated resulting in phosphorylation of three critical tyrosine residues in the IL-2R beta cytoplasmic tail. These phosphorylated residues enable recruitment of the adaptor molecule Shc, activating the MAPK and PI3K pathways, and the transcription factor STAT5. After phosphorylation, STAT5 forms dimers that translocate to the nucleus and initiate gene expression. While STAT5 activation is critical for IL-2 function in most cell types, the contribution of the PI3K/Akt pathway differs between distinct T cell subsets. In Tregs for example, PI3K/Akt is not involved in IL-2 signaling and this may explain some of the different functional outcomes of IL-2 signaling in Tregs vs. effector T cells.
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| definition source |
Pubmed12525482 Pubmed6815536 Pubmed18817510 Pubmed6975347 Pubmed19543225 Reactome, http://www.reactome.org Pubmed3095922 Pubmed17936914 Pubmed18062768 Pubmed3116143 Pubmed1545122 Pubmed3098894
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| label |
Interleukin-2 signaling
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| located_in | ||
| prefixIRI |
HINO:0022232
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| prefLabel |
Interleukin-2 signaling
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| seeAlso |
Reactome Database ID Release 43451927 ReactomeREACT_27283
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| subClassOf | ||
| has_part |
http://purl.obolibrary.org/obo/HINO_0006989 http://purl.obolibrary.org/obo/HINO_0007252 http://purl.obolibrary.org/obo/HINO_0007256 http://purl.obolibrary.org/obo/HINO_0007250 http://purl.obolibrary.org/obo/HINO_0007257 http://purl.obolibrary.org/obo/HINO_0007254 http://purl.obolibrary.org/obo/HINO_0016072 http://purl.obolibrary.org/obo/HINO_0022230 http://purl.obolibrary.org/obo/HINO_0006992 http://purl.obolibrary.org/obo/HINO_0006991 http://purl.obolibrary.org/obo/HINO_0006990 http://purl.obolibrary.org/obo/HINO_0007424 http://purl.obolibrary.org/obo/HINO_0007422 http://purl.obolibrary.org/obo/HINO_0007426 http://purl.obolibrary.org/obo/HINO_0007420 http://purl.obolibrary.org/obo/HINO_0007421 http://purl.obolibrary.org/obo/HINO_0007432 http://purl.obolibrary.org/obo/HINO_0007430 |
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