title: Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells.
abstract: The receptor for leukemia inhibitory factor (LIFR), in combination with the signal-transducing subunit for interleukin-6-type cytokine receptors, gp130, and LIF, activates transcription of acute-phase plasma protein genes in human and rat hepatoma cells and the vasoactive intestinal peptide gene in a human neuroblastoma cell line. To identify the regions within the cytoplasmic domain of LIFR that initiate signal transduction independently of gp130, we constructed a chimeric receptor by linking the extracellular domain of the granulocyte colony-stimulating factor receptor (G-CSFR) to the transmembrane and cytoplasmic domain of human LIFR. The function of the chimeric receptor protein in transcriptional activation was assessed by G-CSF-mediated stimulation of cotransfected cytokine-responsive reporter gene constructs in hepatoma and neuroblastoma cells. By using the full-length cytoplasmic domain and mutants with progressive carboxy-terminal deletions, internal deletions, or point mutations, we identified the first 150 amino acid residues of LIFR as the minimal region necessary for signaling. The signaling reaction appears to involve a cooperativity between the first 70-amino-acid region containing the two sequence motifs conserved among hematopoietin receptors (box 1 and box 2) and a critical sequence between residues 141 and 150 (box 3). Analogous analyses of the cytoplasmic domains of G-CSFR and gp130 indicated similar arrangements of functional domains in these receptor subunits and the requirement of a box 3-related motif for signaling.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: H
authors.initials: H
authors.lastname: Baumann
authors.forename: A J
authors.initials: AJ
authors.lastname: Symes
authors.forename: M R
authors.initials: MR
authors.lastname: Comeau
authors.forename: K K
authors.initials: KK
authors.lastname: Morella
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Friend
authors.forename: S F
authors.initials: SF
authors.lastname: Ziegler
authors.forename: J S
authors.initials: JS
authors.lastname: Fink
authors.forename: D P
authors.initials: DP
authors.lastname: Gearing
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D002460:Cell Line; D050822:Cytokine Receptor gp130; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000235:genetics; D006131:Growth Inhibitors; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008099:Liver / Q000378:metabolism; D008222:Lymphokines; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009474:Neurons / Q000378:metabolism; D051381:Rats; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D015703:Antigens, CD; D006131:Growth Inhibitors; C494199:IL6ST protein, human; C494201:Il6st protein, rat; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D008222:Lymphokines; D008562:Membrane Glycoproteins; D018121:Receptors, Cytokine; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D053606:Receptors, OSM-LIF; D011993:Recombinant Fusion Proteins; D050822:Cytokine Receptor gp130; D004247:DNA