Interaction of IL-2Rβ and γ _c Chains with Jak1 and Jak3: Implications for XSCID and XCID

Abstract

Interleukin-2 (IL-2) signaling requires the dimerization of the IL-2 receptor beta.(IL-2R beta) and common gamma (gamma c) chains. Mutations of gamma c can result in X-linked severe combined immunodeficiency (XSCID). IL-2, IL-4, IL-7 (whose receptors are known to contain gamma c), and IL-9 (whose receptor is shown here to contain gamma c) induced the tyrosine phosphorylation and activation of the Janus family tyrosine kinases Jak1 and Jak3. Jak1 and Jak3 associated with IL-2R beta and gamma c, respectively; IL-2 induced Jak3-IL-2R beta and increased Jak3-gamma c associations. Truncations of gamma c, and a gamma c, point mutation causing moderate X-linked combined immunodeficiency (XCID), decreased gamma c-Jak3 association. Thus, gamma c mutations in at least some XSCID and XCID patients prevent normal Jak3 activation, suggesting that mutations of Jak3 may result in an XSCID-like phenotype.

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…The a-chain has a short C-terminal intracellular segment. Only IL-2Rb and IL-2Rg contribute to intracellular signaling through their long cytoplasmic tails, which contain Box domains that are constitutively associated with inactive Janus kinases JAK1 (IL-2Rb) and JAK3 (IL-2Rg) (Russell et al 1994;Taniguchi et al 1995;Gesbert et al 1998). Capture of IL-2 and binding to/formation of the high-affinity trimer results in activation of JAKs and downstream activation of MAP and STAT5 signaling pathways ( Fig.…”

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

“…This family of cytokines includes IL-2, IL-4, IL-7, IL-9 and IL-15, each of which shares the IL-2 receptor g chain (IL-2Rg) as a receptor component (Giri et al, 1994;Kondo et al, 1993Kondo et al, , 1994Noguchi et al, 1993a;Russell et al, 1993Russell et al, , 1994; Figure 1). Because of its shared nature, IL-2Rg is now known as the common cytokine receptor g chain (g c ) (Leonard, 1996).…”

“…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). Moreover, in addition to its principal interaction with g c , Jak3 also can contact IL2Rb (Zhu et al, 1998).…”

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

“…Each of these receptors, like the IL-2 receptor, consist of three subunits, termed a, b and g. Of these, the a subunit acts as the ligand binding subunit, while the b and g subunits function as signal transducing subunits. The IL-2Rg chain associates with JAK3 and mutations in both IL-2Rg chain and JAK 3 results in a nonfunctional receptor, which abrogates signaling via IL-2, IL-7, IL-9 and IL-15 (Russell et al, 1994(Russell et al, , 1995.…”