PT Unknown
AU Suthaus, J
TI Ligand-independent gp130-type receptor activation by forced homo- and heterodimerization
PY 2010
PU Christian-Albrechts-Universität zu Kiel
WP https://macau.uni-kiel.de/receive/diss_mods_00005492
LA en
DE Ligand-independent receptor activation; gp130-type receptors; homodimers; heterodimers; IL-6-like cytokines; Liganden-unabhängige Rezeptorenaktivierung; gp130-ähnliche Rezeptoren; Homodimere; Heterodimere; IL-6-ähnliche Zytokine
AB The IL-6 family of cytokines consists of IL-6, vIL-6, IL-11, IL-27, CNTF, CT-1, LIF, CLC, NP, OSM, and IL-31. IL-6, vIL-6, IL-11 induce the formation of a gp130-homodimer, whereas signaling by CNTF, CT-1, LIF, CLC, and NP results in the formation of a gp130/LIFR heterodimer. OSM can induce the formation of a dimer of gp130 with LIFR or the related protein OSMR. IL-27 exclusively signals via a heterodimer comprising gp130 and WSX-1, whereas IL-31 induces the formation of an OSMR/GPL heterodimer. Interestingly, naturally occurring, ligand-independent, and constitutively active gp130 variants were described to play a role in the onset of inflammatory hepatocellular adenomas. In the past, constitutively active gp130 variants based on homodimerization of Jun leucine zippers were generated in this laboratory. However, using a Fos leucine zipper-gp130 (Fos-gp130) chimera and a Jun leucine zipper-WSX-1 chimera (Jun-WSX-1), Fos and Jun form the AP-1 transcription factor complex, revealed that also Fos-gp130 alone was able to induce ligand-independent STAT3 phosphorylation and ligand-independent growth of cytokine-dependent cells indicating that this approach was not suitable for the generation of ligand-independent, constitutive activation of heterodimeric receptors. Therefore a novel IL-15/IL-15Rα based system to generate ligand-independent, constitutively active heterodimeric complexes for all known gp130-receptor members was developed. In this system, IL-15 was genetically fused to one receptor component whereas IL-15Rα was fused to the second receptor component. Ligand-independent heterodimerization of gp130 with WSX-1, LIFR and OSMR and of OSMR with GPL led to constitutive, ligand-independent STAT1 and/or STAT3 and ERK1/2 phosphorylation. Moreover, these receptor combinations induced transcription of the STAT3 target genes c-myc and Pim-1 upon stable transfection and conferred to independent growth of cytokine-dependent cells. The IL-15/IL-15Rα system is established as a novel system to mimic constitutive and ligand-independent activation of homo- and heterodimeric receptor complexes, which could also be applicable to other heterodimeric cytokine receptor and growth factor receptor families. Additionally, in an improved approach a mutated IL-15 protein was used, which was still able to bind the IL-15R-sushi domain, but not to IL-2Rβ and IL-2Rγc receptor chains. In combination with the 2A peptide technology, this is the first step towards to translation of the in vitro data to analyse the tumorigenic potential of gp130-heterodimeric receptor complexes in vivo.
PI Kiel
ER