Format

Send to

Choose Destination
Mol Biol Cell. 2016 Jul 15;27(14):2301-16. doi: 10.1091/mbc.E14-12-1645. Epub 2016 May 18.

Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases.

Author information

1
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, D-40225 Düsseldorf, Germany doreen.floss@uni-duesseldorf.de jscheller@uni-duesseldorf.de.
2
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
3
Institute of Animal Breeding and Genetics/Biomodels Austria, University of Veterinary Medicine, A-1210 Vienna, Austria.
4
Medical Clinic II, Division of Hepatology, University Hospital Würzburg, D-97080 Würzburg, Germany.

Abstract

The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor β1 (IL-12Rβ1) as one component of their receptor signaling complexes, with IL-12Rβ2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12Rβ1, whereas Jak2 binds to IL-23R and also to IL-12Rβ2. Receptor association of Jak2 is mediated by Box1 and Box2 motifs located within the intracellular domain of the receptor chains. Here we define the Box1 and Box2 motifs in IL-12Rβ1 and an unusual Jak2-binding site in IL-23R by the use of deletion and site-directed mutagenesis. Our data show that nonfunctional box motifs abolish IL-12- and IL-23-induced STAT3 phosphorylation and cytokine-dependent proliferation of Ba/F3 cells. Coimmunoprecipitation of Tyk2 by IL-12Rβ1 and Jak2 by IL‑23R supported these findings. In addition, our data demonstrate that association of Jak2 with IL-23R is mandatory for IL-12 and/or IL-23 signaling, whereas Tyk2 seems to be dispensable.

PMID:
27193299
PMCID:
PMC4945146
DOI:
10.1091/mbc.E14-12-1645
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center