Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2

Abstract

Interleukin-2 is an autocrine growth factor for T cells which also activates other cells including B cells and natural killer cells. The subunits of the interleukin-2 receptor (IL-2R) lack intrinsic enzymatic activity, but protein tyrosine phosphorylation is a critical event following ligand binding and src family kinases, such as Lck, are known to be activated by IL-2 (refs 5-9). However, IL-2 signalling can occur in the absence of receptor interaction with Lck, suggesting that other protein tyrosine kinases might be important. Here we report that a new member of the Janus family of kinases (Jak-3) is coupled to the IL-2R in human peripheral blood T cells and natural killer cells.

Effect of Anti‐IL‐2Rα Antibody on IL‐2‐induced Jak/STAT Signaling

“…The Jaks are activated within minutes of IL-2 binding (7,8,17). Jak1 associates with the ILTkaczuk et al (Figure 2A, pJak1 or pJak3).…”

“…In this study we evaluated one pathway known to be critical for Tcell proliferation, the Jak/STAT pathway. The janus family of protein tyrosine kinases (Jaks) and signal transducers and activators of transcription (STAT) proteins are rapidly activated upon IL-2R ligation (7,8). Jak1 and Jak3 molecules bind to IL-2Rb and g chain subunits and activate STAT5a/b proteins.…”

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

“…As is typical of type I cytokine receptors, neither IL-2Rb nor g c contains protein kinase activity in its cytoplasmic domain (Hatakeyama et al, 1989;Takeshita et al, 1992). However, within minutes following the interaction of IL-2 with the high-or intermediate-a nity IL-2 receptors, a number of cellular proteins, including IL2Rb and g c , are phosphorylated on tyrosine residues (Farrar and Ferris, 1989;Turner et al, 1991), at least in part by the receptor-associated protein tyrosine kinases, Jak1 and Jak3 (Friedmann et al, 1996;Johnston et al, 1994;Witthuhn et al, 1994). It has been demonstrated that in the absence of IL-2, Jak1 is associated with IL-2Rb Russell et al, 1994;Witthuhn et al, 1994) and Jak3 is with g c Russell et al, 1994;Figure 2).…”

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

“…Both cytokines share a pair of receptor subunits, the gamma chain common to several cytokine receptors (γ c , CD132) combined with the IL-2/15 beta receptor chain (IL-2Rβ, CD122) [11]. Binding of either IL-2 or IL-15, with Kd's ~10 −9 M [12, 13,14], will activate this dimeric receptor to transmit intracellular signals via the JAK1/3-STAT3/5 pathways [15,16,17]. There are substantial numbers of these CD122/CD132 receptors on T cells and, at high concentrations (10 −8 M) of either IL-2 or IL-15, these receptors will be saturated.…”