Leukemia Inhibitory Factor (LIF), Cardiotrophin-1, and Oncostatin M Share Structural Binding Determinants in the Immunoglobulin-like Domain of LIF Receptor

Plun‐Favreau, Hélène; Perret, David; Diveu, Caroline; Froger, Josy; Chevalier, Sylvie; Lelièvre, Éric; Gascan, Hugues; Chabbert, Marie

doi:10.1074/jbc.m303168200

Cited by 49 publications

(48 citation statements)

References 92 publications

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“…In many cell types, exogenous LIF upregulates LIFR mRNA expression [81,82]. In contrast, we observed that in response to LIF stimulation in NP cells, LIFR expression remained unchanged, but gp130 mRNA was upregulated in a concentration-dependent fashion (Fig.…”

Section: Signaling Pathways Activated By Lifcontrasting

confidence: 42%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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Various growth factor cocktails have been used to proliferate and then differentiate human neural progenitor (NP) cells derived from embryonic stem cells (ESC) for in vitro and in vivo studies. However, the cytokine leukemia inhibitory factor (LIF) has been largely overlooked. Here, we demonstrate that LIF significantly enhanced in vitro survival and promoted differentiation of human ESC-derived NP cells. In NP cells, as well as NP-derived neurons, LIF reduced caspase-mediated apoptosis and reduced both spontaneous and H 2 O 2 -induced reactive oxygen species in culture. In vitro, NP cell proliferation and the yield of differentiated neurons were significantly higher in the presence of LIF. In NP cells, LIF enhanced cMyc phosphorylation, commonly associated with self-renewal/proliferation. Also, in differentiating NP cells LIF activated the phosphoinositide 3-kinase and signal transducer and activator of transcription 3 pathways, associated with cell survival and reduced apoptosis. When differentiated in LIF 1 media, neurite outgrowth and ERK1/2 phosphorylation were potentiated together with increased expression of gp130, a component of the LIF receptor complex. NP cells, pretreated in vitro with LIF, were effective in reducing infarct volume in a model of focal ischemic stroke but LIF did not lead to significantly improved initial NP cell survival over nontreated NP cells. Our results show that LIF signaling significantly promotes human NP cell proliferation, survival, and differentiation in vitro. Activated LIF signaling should be considered in cell culture expansion systems for future human NP cell-based therapeutic transplant studies.

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Section: Signaling Pathways Activated By Lifcontrasting

confidence: 42%

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

et al. 2012

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“…Structural analyses of this family of receptors revealed that high affinity binding of the cytokine to its receptor complex involves on one side the CBD of a first receptor subunit and on the other side the Ig-like domain of the second receptor component (50 -54). We previously reported that OSM binds to the CBD of gp130 and to the Ig-like domain of OSMR (52,55). In the soluble form of OSMR, the CBD located downstream from the Ig-like domain was truncated and stopped after half of the module, suggesting that this truncated portion of receptor is not able to bind a cytokine.…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Diveu¹,

Véneréau

Froger

et al. 2006

Journal of Biological Chemistry

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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 immunoglobulinlike 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. Oncostatin M (OSM)3 was originally isolated from culture supernatant of U937 histiocytic leukemia cells based on its ability to inhibit the proliferation of the A375 melanoma cell line (1, 2). OSM is produced by activated monocyte, T lymphocyte, and dendritic cell types and is also described as a potent inducer of inflammation (3)(4)(5)(6)(7)(8). OSM belongs to the interleukin-6 cytokine family also encompassing IL-11, IL-27, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (9 -12).The cytokines of the IL-6 family use two-or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13-14). These receptors belong to the type I cytokine receptors, characterized by the presence of at least one cytokine binding domain (CBD) with conserved cysteine positions and a WSXWS motif (15). All the receptor complexes belonging to the IL-6 cytokine family share the common gp130 signaling receptor subunit in the formation of their multimeric receptors (16). Depending on the ligand, gp130 can either homodimerize in the presence of IL-6 or IL-11 (17, 18) or heterodimerize with related type I cytokine receptors such as LIFR, IL-27R, or OSMR when recruited by other members of the IL-6 family of cytokines (19 -21).In humans, OSM signal transduction occurs via two distinct receptor complexes. The type I OSM receptor consists of the low affinity chain, LIFR, associated to gp130 (19). This type I receptor can indifferently bind LIF or OSM. Through this mechanism, OSM elicits biological activities overlapping with those induced by LIF, such as hepatocyte activation, bone renewal, or the in vitro maintenance of embryonic stem cell phenotype (22).The type II OSM receptor, specifically recognizing OSM, associa...

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“…Then, the CBD of some large-size cytokine receptors (gp130, IL-12R␤1, and granulocyte-colony stimulating factor) interact with the cytokine(s) through site II (57,(61)(62)(63)(64). Recruitment of an additional site of interaction (site III) located on the Ig-like domain of a second large-size receptor leads to oligomerization and signaling of the receptor complex (65)(66)(67)(68)(69). Because no Ig-like domain is present in GPL, we can hypothesize that GPL should interact with its potential ligand(s) through a site II or a site I. GPL also likely implicates a neighbor receptor holding an Ig-like module to define the site III and to allow the dimerization process of large-size signaling subunits and subsequent signaling events.…”

Section: Discussionmentioning

confidence: 99%

GPL, a Novel Cytokine Receptor Related to GP130 and Leukemia Inhibitory Factor Receptor

Diveu

Lelièvre

Perret

et al. 2003

Journal of Biological Chemistry

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105

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We describe a novel cytokine receptor named GP130 Like receptor, or GPL, that displays similarities with the interleukin-6 and interleukin-12 family of signaling receptors. Four different isoforms diverging in their carboxyl terminus were isolated, corresponding to proteins encompassing 560, 610, 626, and 745 amino acids. Sequences included a signal peptide of 32 amino acids, followed by a cytokine binding domain containing four conserved cysteines, a WSDWS motif, and a region consisting of three fibronectin type III domain repeats. No immunoglobulin-like module was identified in the GPL sequences. The intracellular part of longer isoforms contained a proline-rich region defining a box1 motif for interaction with the Janus kinases. The Gpl gene is organized in 15 exons and is located on 5q11.2 in tandem with the gp130 gene. Both genes were only separated by 24 kilobases, with opposite transcriptional orientations. The GPL receptor displayed a 28% identity with gp130. Specific GPL transcripts were observed in tissues involved in reproduction. Transcripts were also found in blood cells and in bone marrow, revealing expression of GPL in all of the myelomonocytic lineage, from hematopoietic stem cells to activated dendritic cells. In monocytes and dendritic cells, expression of GPL was strongly up-regulated by interferon-␥, indicating a possible involvement of GPL in Th1-type immune responses. The molecular basis of cell signaling mediated by GPL was studied using chimeric receptors where external portions of ␣ or ␤ interleukin-5 receptor subunits were fused to the internal portion of GPL or of related receptors. Results indicated that association of GPL to the intracellular portions of gp130, or LIF receptor, allowed the signaling cascade.

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Leukemia Inhibitory Factor (LIF), Cardiotrophin-1, and Oncostatin M Share Structural Binding Determinants in the Immunoglobulin-like Domain of LIF Receptor

Abstract: Leukemia inhibitory factor (LIF),

Cited by 49 publications

References 92 publications

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

GPL, a Novel Cytokine Receptor Related to GP130 and Leukemia Inhibitory Factor Receptor

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