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*
Department of Biochemistry, Rheinisch-Westfälische Technische Hochschule Aachen, Germany; and
Department of Medical Protein Chemistry, Flanders Interuniversity Institute for Biotechnology, University of Ghent, Ghent, Belgium
Leukemia inhibitory factor (LIF), cardiotrophin-1, ciliary
neurotrophic factor, and oncostatin M (OSM) lead to heterodimerization
of LIF receptor (LIFR) or the OSM-specific receptor (OSMR) with
glycoprotein (gp) 130, the common receptor subunit for IL-6-type
cytokines. Thereby intracellular signaling via Janus kinases (Jaks) and
STAT transcription factors is initiated. We investigated the
contributions of LIFR and OSMR to signal transduction in the context of
heterodimers with gp130. Chimeric receptors based on the extracellular
parts of the IL-5R 
- and ß-chains were generated, allowing the
induced heterodimerization of two different cytoplasmic tails. Our
studies demonstrate that upon heterodimerization with the gp130
cytoplasmic region, the cytoplasmic parts of both LIFR and OSMR were
critical for activation of an acute phase protein promoter in HepG2
hepatoma cells. The membrane-proximal region of LIFR or OSMR was
crucial for the ability of such receptor complexes to induce DNA
binding of STAT1 and STAT3 in COS-7 cells. Membrane-distal regions of
LIFR and OSMR contributed to STAT activation even in the absence of
gp130 STAT recruitment sites. We further show that the Janus kinases
Jak1 and Jak2 constitutively associated with receptor constructs
containing the cytoplasmic part of LIFR, OSMR, or gp130, respectively.
Homodimers of the LIFR or OSMR cytoplasmic regions did not elicit
responses in COS-7 cells but did in HepG2 cells and in MCF-7 breast
carcinoma cells. Thus, in spite of extensive functional similarities,
differential signaling abilities of gp130, LIFR, and OSMR may become
evident in a cell-type-specific manner.
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