Contributions of leukemia inhibitory factor receptor and oncostatin M receptor to signal transduction in heterodimeric complexes with glycoprotein 130.
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 alpha- and beta-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.
Hermanns
H M
HM
Department of Biochemistry, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Radtke
S
S
Haan
C
C
Schmitz-Van de Leur
H
H
Tavernier
J
J
Heinrich
P C
PC
Behrmann
I
I
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019556:COS Cells; D006528:Carcinoma, Hepatocellular; D050822:Cytokine Receptor gp130; D003593:Cytoplasm / Q000378:metabolism / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors; D006801:Humans; D015850:Interleukin-6; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053683:Oncostatin M; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018123:Receptors, Interleukin / Q000378:metabolism; D053649:Receptors, Interleukin-5; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; C508351:OSM protein, human; D010446:Peptide Fragments; D010455:Peptides; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2