JAK1 phosphorylates Y338, Y392 and Y510 of IL2RB Phosphorylation of IL2RB Y338 enables SHC recruitment Phosphorylation of IL2RB Y338, Y392 or Y510 enables STAT recruitment SHC1 bound to IL2 receptor is phosphorylated IL2RB associates with JAK1 Interleukin-2 receptor alpha binds interleukin-2 IL2RG associates with JAK3 Interleukin-2: IL2 receptor alpha:beta binds IL2 receptor gamma subunit Interleukin-2 receptor alpha:IL2 binds Interleukin-2 receptor beta Within the IL-2R complex JAK3 phosphorylates JAK1 Recruited STAT5 is phosphorylated STAT5 dimers translocate to the nucleus and bind to specific DNA sequences Syk binds IL2RB Phosphorylated STAT5 is released Phosphorylated STAT5a/b form dimers Pyk2 is activated following IL2 stimulation SYK is a substrate for JAK1 Pyk2 associates with Jak3 RAF/MAP kinase cascade PathwayStep7140 PathwayStep7141 PathwayStep7142 PathwayStep7152 PathwayStep7153 PathwayStep7150 PathwayStep7151 PathwayStep7156 PathwayStep7157 PathwayStep7154 PathwayStep7155 PathwayStep7158 PathwayStep7133 PathwayStep7135 PathwayStep7134 PathwayStep7137 PathwayStep7136 PathwayStep7139 PathwayStep7138 Interleukin receptor SHC signaling Interleukin-2 signaling 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. Pubmed12525482 Pubmed1545122 Pubmed17936914 Pubmed18062768 Pubmed18817510 Pubmed19543225 Pubmed3095922 Pubmed3098894 Pubmed3116143 Pubmed6815536 Pubmed6975347 Reactome Database ID Release 43451927 Reactome, http://www.reactome.org ReactomeREACT_27283 Reviewed: Dooms, H, 2011-03-17 Reviewed: Villarino, A, 2011-02-11 PathwayStep3857