Influence of subunit combinations on signaling by receptors for oncostatin M, leukemia inhibitory factor, and interleukin-6.
Oncostatin M (OSM), leukemia inhibitory factor (LIF), and interleukin-6 (IL-6) induce expression of a similar set of acute phase plasma protein genes in hepatic cells. The redundant action of these cytokines has been ascribed to the involvement of the common signal-transducing receptor subunit, gp130, in combination with cytokine-specific, ligand-binding subunits. To define the specificity of the signal transduction by the LIF/OSM receptor (a heterodimer of gp130 and LIF receptor (LIFR)) and the OSM-specific receptor (a heterodimer of gp130 and OSM receptor (OSMR)), we reconstituted the receptor function by transfection into receptor-negative Hep3B hepatoma cells. Both receptors activate DNA binding activity of STAT1, -3, and -5B and induce gene transcription through IL-6-responsive elements. The signaling-competent cytoplasmic domain regions of OSMR and LIFR were defined by the analysis of progressive carboxyl-terminal deletion constructs. The 36 residue carboxyl-terminal region containing the distal box 3 sequence motif of OSMR is required for signal transduction by the OSM-specific receptor. In contrast, signaling by LIFR did not display the same requirement for receptor domains and was not strictly dependent on the box 3 elements. The signaling by endogenous LIF and OSM receptors differed from that by IL-6R by the prominent activation of STAT5 as shown in the mouse hepatoma cell line, Hepa-1. The data suggest that the signaling specificity of the receptors for the three cytokines is determined by the composition of the cytoplasmic domains associated in the signal-competent receptor complex and that the signaling is not identical among these cytokine receptors.
Kuropatwinski
K K
KK
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
De Imus
C
C
Gearing
D
D
Baumann
H
H
Mosley
B
B
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism; D006131:Growth Inhibitors; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D051379:Mice; D008894:Milk Proteins; D018121:Receptors, Cytokine / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D008894:Milk Proteins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D053606:Receptors, OSM-LIF; D053677:Receptors, Oncostatin M; D050799:STAT5 Transcription Factor; D015534:Trans-Activators