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The IL-2 receptor is a key component of immune signaling and is required for the activation, proliferation, and survival of T cells. This receptor is composed of three polypeptide chains, the alpha, beta, and gamma chains. The IL-2 receptor gamma chain is a common component for several other cytokine receptors, including IL-4, IL-7, IL-9 and IL-15. The IL-2 receptor beta chain is essential for IL-2 signaling and is also a component of the IL-15 receptor complex. The polypeptides of the IL-2 receptor do not themselves have intrinsic catalytic activity, but interact with cytoplasmic signaling proteins to transduce signals. Different regions of the cytoplasmic domain of the IL-2 receptor beta chain interact and couple with distinct signaling pathways and cellular responses. JAK1 associates with the beta chain and JAK3 with the gamma chain. Binding of IL-2 induces heterodimerization of receptor subunits, and activation of JAK kinase activity. Tyrosine residues in the beta chain cytoplasmic domain are phosphorylated during activation, recruiting other factors to the phosphorylated tyrosine residues through src homology 2 (SH2) domains. The adaptor protein Shc binds to phosphorylated tyrosine 338 of the beta chain. When bound, Shc is phosphorylated and couples through Grb2 and Sos-1 to activate Ras and stimulate T cell proliferation. Another key proliferative pathway activated by IL-2 is phosphorylation of STAT-5 by JAK kinases. STAT-5 is recruited to IL-2 beta phosphorylated tyrosines at multiple positions, including Y338, Y392 and Y510. Once phosphorylated, STAT-5 enters the nucleus to regulate the transcription of several genes, some proliferative, such as cyclin genes, and others that are involved in T cell immune function such as cytokine genes. The suppressors of cytokine activation, SOCS-3 and SOCS-1, oppose phosphorylation and activation of STAT-5 and JAK1 caused by IL-2. PI3 kinase is another protein recruited to IL-2 receptor beta chain tyrosines when phosphorylated. Activation of PI3 Kinase also contributes to the proliferative activity of IL-2 in T cells. The role of other tyrosines in the IL-2 receptor beta chain, Y355, Y358 and Y361, is not yet clear, but may be involved in signaling by the protein kinase p56lck. In addition to stimulating T cell activation and proliferation, IL-2 activation blocks T cell apoptosis through multiple pathways. Among the genes activated by STAT-5 are BCL-xL, an inhibitor of apoptosis, and fas-ligand, an activator of apoptosis in cells expressed the fas receptor. PI3 kinase also contributes to anti-apoptotic activity of IL-2 through AKT activation. T cell responses to IL-2 must be coordinated in part in the complex protein-protein interactions with the IL-2 receptor beta chain. (This definition may be outdated - see the DesignNote.)
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