ABSTRACT
Several neurotropic cytokines relay their signaling through the leukemia inhibitory factor receptor. This 190kDa subunit couples with the 130kDa gp130 subunit to transduce intracellular signaling in neurons and oligodendrocytes that leads to expression of genes associated with neurosurvival. Moreover, activation of this receptor alters the phenotype of immune cells to an anti-inflammatory one. Although cytokines that activate the leukemia inhibitory factor receptor have been studied in the context of neurodegenerative disease, therapeutic targeting of the specific receptor subunit has been understudied in by comparison. This review examines the role of this receptor in the CNS and immune system, and its application in the treatment in stroke and other brain pathologies.
Subject(s)
Neuroprotection , Receptors, OSM-LIF/metabolism , Animals , Ciliary Neurotrophic Factor/metabolism , Cytokines/metabolism , Humans , Neurodegenerative Diseases/metabolism , Receptors, OSM-LIF/chemistry , Signal TransductionABSTRACT
gp130 is a shared receptor for at least nine cytokines and can signal either as a homodimer or as a heterodimer with Leukemia Inhibitory Factor Receptor (LIF-R). Here, we biophysically and structurally characterize the full-length, transmembrane form of a quaternary cytokine receptor complex consisting of gp130, LIF-R, the cytokine Ciliary Neurotrophic Factor (CNTF), and its alpha receptor (CNTF-Ralpha). Thermodynamic analysis indicates that, unlike the cooperative assembly of the symmetric gp130/Interleukin-6/IL-6Ralpha hexameric complex, CNTF/CNTF-Ralpha heterodimerizes gp130 and LIF-R via noncooperative energetics to form an asymmetric 1:1:1:1 complex. Single particle electron microscopic analysis of the full-length gp130/LIF-R/CNTF-Ralpha/CNTF quaternary complex elucidates an asymmetric structural arrangement, in which the receptor extracellular and transmembrane segments join as a continuous, rigid unit, poised to sensitively transduce ligand engagement to the membrane-proximal intracellular signaling regions. These studies also enumerate the organizing principles for assembly of the "tall" class of gp130 family cytokine receptor complexes including LIF, IL-27, IL-12, and others.
Subject(s)
Cytokine Receptor gp130/chemistry , Multiprotein Complexes/chemistry , Protein Structure, Quaternary , Receptors, OSM-LIF/chemistry , Signal Transduction/physiology , Animals , Ciliary Neurotrophic Factor/chemistry , Ciliary Neurotrophic Factor/genetics , Ciliary Neurotrophic Factor/metabolism , Crystallography, X-Ray , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Humans , Models, Molecular , Molecular Sequence Data , Multiprotein Complexes/ultrastructure , Receptor, Ciliary Neurotrophic Factor/chemistry , Receptor, Ciliary Neurotrophic Factor/genetics , Receptor, Ciliary Neurotrophic Factor/metabolism , Receptors, OSM-LIF/genetics , Receptors, OSM-LIF/metabolism , ThermodynamicsABSTRACT
Leukemia inhibitory factor (LIF) receptor is a cell surface receptor that mediates the actions of LIF and other IL-6 type cytokines through the formation of high-affinity signaling complexes with gp130. Here we present the crystal structure of a complex of mouse LIF receptor with human LIF at 4.0 A resolution. The structure is, to date, the largest cytokine receptor fragment determined by x-ray crystallography. The binding of LIF to its receptor via the central Ig-like domain is unlike other cytokine receptor complexes that bind ligand predominantly through their cytokine-binding modules. This structure, in combination with previous crystallographic studies, also provides a structural template to understand the formation and orientation of the high-affinity signaling complex between LIF, LIF receptor, and gp130.
Subject(s)
Immunoglobulins/chemistry , Immunoglobulins/metabolism , Leukemia Inhibitory Factor/chemistry , Leukemia Inhibitory Factor/metabolism , Receptors, OSM-LIF/chemistry , Receptors, OSM-LIF/metabolism , Animals , Crystallography, X-Ray , Cytokine Receptor gp130/chemistry , Cytokine Receptor gp130/metabolism , Humans , Immunoglobulins/genetics , Immunoglobulins/immunology , Interleukin-6/chemistry , Interleukin-6/metabolism , Leukemia Inhibitory Factor/genetics , Leukemia Inhibitory Factor/immunology , Ligands , Mice , Models, Molecular , Protein Binding , Protein Structure, Quaternary , Protein Structure, Tertiary , Receptors, OSM-LIF/genetics , Receptors, OSM-LIF/immunology , Signal TransductionABSTRACT
Activation of the signaling transduction pathways mediated by oncostatin M (OSM) requires the binding of the cytokine to either type I OSM receptor (leukemia inhibitory factor receptor/gp130) or to type II OSM receptor (OSMR/gp130). In the present work we have developed an enzyme-linked immunosorbent assay detecting a soluble form of OSMR (sOSMR) secreted by glioblastoma, hepatoma, and melanoma tumor cell lines. sOSMR was also present in sera of healthy individuals, with increased levels in multiple myeloma. Molecular cloning of a corresponding cDNA was carried out, and it encoded for a 70-kDa protein consisting of a half cytokine binding domain containing the canonical WSXWS motif, an immunoglobulin-like domain, and the first half of a second cytokine binding domain with cysteines in fixed positions. Analysis of the soluble receptor distribution revealed a preferential expression in lung, liver, pancreas, and placenta. sOSMR was able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties. We have also shown that OSM could positively regulate the synthesis of its own soluble receptor in tumor cells.
Subject(s)
Cytokine Receptor gp130/physiology , Interleukins/physiology , Oncostatin M/physiology , Receptors, OSM-LIF/physiology , Alternative Splicing , Amino Acid Motifs , Amino Acid Sequence , Base Sequence , Cell Line, Tumor , Cytokine Receptor gp130/chemistry , Glycoside Hydrolases/metabolism , Humans , Interleukins/chemistry , Molecular Sequence Data , Oncostatin M/chemistry , Protein Binding , Protein Structure, Tertiary , Receptors, OSM-LIF/chemistry , Tissue DistributionABSTRACT
OBJECTIVE: To investigate the mechanism of disordered proliferation of leukemic cells and the proliferation inhibition by the Fas death domain (FASDD) in human leukemia cell line Meg-01. METHODS: The chimerical receptors (Fas/190, Fas/130) were constructed by Fas cytoplasmic domain with the leukemic inhibitory factor (LIF) receptor subunits gp190 and gp130, another chimerical receptor was constructed by replacing the gp130 in Fas/130 with Fas death domain (FAS/130f). The chimerical receptors were separately expressed on the membrane of Meg-01, and activated with anti-Fas antibodies to induce the oligomerics of the cytoplasmic regions (190cyt-190cyt-190cyt, 130cyt-130cyt-130cyt or FASDD-FASDD-FASDD) for initiating the intracellular signal transduction. c-myc expression level was assayed by means of immunoblotting and immunobiochemistry. RESULTS: Increased c-myc expression and cell proliferation were observed in the group of Fas/130 as compared with the other two groups. CONCLUSION: The cytoplasmic domain of gp130 might involve the induction of c-myc expression and the cell proliferation of Meg-01 cell. The Fas death domain may be a medium in the apoptosis induction against the effect of gp130.
