Characterization of the Cytoplasmic Domain of Interleukin-13 Receptor-α

Interleukin (IL)-13 and IL-4 are pleiotropic immunoregulatory cytokines that share many overlapping biological properties reflecting the fact that both can utilize a receptor complex composed of the IL-4 receptor-α (IL-4Rα) chain and the IL-13Rα chain. The cytoplasmic domain of the IL-13Rα is 60 amino acids long and is essential for IL-13-dependent growth. It contains a Pro-rich domain in the membrane-proximal region and two Tyr residues. Here we show that a truncated IL-13Rα, lacking the 38 carboxyl-terminal residues but retaining the Pro-rich region, can support IL-13-dependent proliferation, although with reduced efficiency. A Y402F mutant of the cytoplasmic domain of IL-13Rα supported normal IL-13-induced growth. However, tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3), which we show is induced by IL-13 and IL-4 in cells that express the IL-13Rα, was significantly reduced. The cytoplasmic domain of IL-13Rα was constitutively associated with STAT3, Tyk2, and Janus kinase 1 (JAK1). IL-13-induced tyrosine phosphorylation of IL-13Rα in vivo could not be detected using anti-Tyr(P) antibodies. A glutathione S-transferase fusion protein of the cytoplasmic domain of IL-13Rα was phosphorylated on tyrosinein vitro by JAK1, JAK3, and Tyk2, although the tyrosine phosphorylation events mediated by Tyk2 and JAK3 were not detectable using anti-phosphotyrosine antibodies. These data, together with the demonstration that IL-13Rα associates constitutively with Tyk2 and that Tyr-402 is involved in IL-13-induced phosphorylation of STAT3, suggest that the latter is mediated by Tyk2. Tyrosine phosphorylation of STAT3, which was not necessary for IL-13-induced proliferation, may account for some of the effects of IL-4 and IL-13 on the function of their targets.