A third subunit, the gamma chain, of the human interleukin-2 receptor (IL-2R) was identified, and a complementary DNA clone encoding this member of the cytokine receptor family was isolated. The gamma chain is necessary for the formation of the high- and intermediate-affinity receptors, which consists of alpha beta gamma heterotrimers and beta gamma heterodimers, respectively. The IL-2R on murine fibroblastoid cells can be internalized after binding IL-2 only if the gamma chain is present; alpha and beta are insufficient for internalization. Thus, the gamma chain is an indispensable component of the functional IL-2R.

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for IL-4, IL-7, IL-9, and IL-15 as well as IL-2. Here we show that the gamma(c) is also shared with the IL-21R complex. Although IL-21 binds to the IL-21R expressed on gamma(c)-deficient ED40515(-) cells, IL-21 is unable to transduce any intracytoplasmic signals. However, in EDgamma-16 cells, a gamma(c)-transfected ED40515(-) cell line, IL-21 binds to the IL-21R and can activate Janus kinase (JAK)1, JAK3, STAT1, and STAT3. The chemical cross-linking study reveals the direct binding of IL-21 to the gamma(c). These data clearly demonstrate that the gamma(c) is an indispensable subunit of the functional IL-21R complex.

Interleukin 2 (IL-2), a T cell-derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the alpha, beta and gamma chains, or the beta and gamma chains. The third component, the gamma chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor, together with the beta chain, the gamma chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same gamma chain as an essential subunit. Interestingly, mutations of the gamma chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the gamma chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the gamma chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the gamma chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.

We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.Activation of tyrosine kinases is an initial biochemical event in intracellular signal transduction from cytokine receptors after their bindings with ligands. Although most of the cytokine receptors do not contain any consensus motif of tyrosine kinase, several families of tyrosine kinases, such as the Src family tyrosine kinases, Jak family tyrosine kinases, Syk/ZAP70 family tyrosine kinases, and other family tyrosine kinases (Fes and Tec), are known to be associated with the cytoplasmic domains of cytokine receptors (1). Upon activation of the tyrosine kinases, cytokine receptor subunits are phosphorylated on tyrosine residues, which results in association of the receptor subunits with signal transducers and activators of transcription (Stats) 1 via interaction between the phosphorylated tyrosine residues of receptor subunits and the Src homology 2 (SH2) domains of Stats, and subsequently the Stats are tyrosinephosphorylated by the Jak family tyrosine kinases to be activated as transcription factors (2, 3). For example, interleukin-2 (IL-2) induces activation of Lck (Fyn or Lyn), Syk, and Jak1, all of which are associated with the IL-2 receptor ␤ chain, and Jak3, which is associated with the IL-2 receptor ␥c chain, together with activation of other signaling molecules such as phosphatidylinositol 3-kinase and Shc/Grb2/Sos/Ras/Raf1/mitogen-activated protein kinase cascade (4). Stat5 associated with the IL-2 receptor ␤ chain is activated by Jak3 but not Jak1 upon IL-2 stimulation (5-7). IL-3/granulocyte-macrophage colony-stimulating factor (GM-CSF) also seems to activate Stat5 through Jak2 (8, 9). Activation of Stat5 has been shown to be involved in signaling for DNA synthesis mediated by IL-2 and IL-3 in certain cell lines (10, 11). Jak3 and Jak2 are also known to be essential for induction of c-myc and c-fos upon stimulation with IL-2 and GM-CSF, respective...

No abstract