CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex

Elson, Greg; Lelièvre, Éric; Guillet, Catherine; Chevalier, Sylvie; Plun‐Favreau, Hélène; Froger, Josy; Suard, I.; Coignac, Amélie Benoit de; Delneste, Yves; Bonnefoy, Jean‐Yves; Gauchat, Jean‐François; Gascan, Hugues

doi:10.1038/78765

Cited by 230 publications

(279 citation statements)

References 32 publications

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“…The role of the CLF-1 on cell proliferation is not yet documented. This recently discovered growth factor associates with the cardiotrophin-like cytokine (CLC) to form a heterodimeric cytokine that binds and activates the trimeric complex constituted of the CNTFR receptor, the leukemia-inhibitory factor receptor and gp130 (Elson et al, 1998(Elson et al, , 2000. Although the signaling cascade resulting from the binding to the receptor is already well defined (Lelievre et al, 2001), the role of the CLF-1 factor in terms of cellular responses has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Microarray screening for target genes of the proto-oncogene PLAG1

et al. 2004

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PLAG1 is a proto-oncogene whose ectopic expression can trigger the development of pleomorphic adenomas of the salivary glands and of lipoblastomas. As PLAG1 is a transcription factor, able to activate transcription through the binding to the consensus sequence GRGGC(N) 6-8 GGG, its ectopic expression presumably results in the deregulation of target genes, leading to uncontrolled cell proliferation. The identification of PLAG1 target genes is therefore a crucial step in understanding the molecular mechanisms involved in PLAG1-induced tumorigenesis. To this end, we analysed the changes in gene expression caused by the conditional induction of PLAG1 expression in fetal kidney 293 cell lines. Using oligonucleotide microarray analyses of about 12 000 genes, we consistently identified 47 genes induced and 12 genes repressed by PLAG1. One of the largest classes identified as upregulated PLAG1 targets consists of growth factors such as the insulin-like growth factor II and the cytokinelike factor 1. The in silico search for PLAG1 consensus sequences in the promoter of the upregulated genes reveals that a large proportion of them harbor several copies of the PLAG1-binding motif, suggesting that they represent direct PLAG1 targets. Our approach was complemented by the comparison of the expression profiles of pleomorphic adenomas induced by PLAG1 versus normal salivary glands. Concordance between these two sets of experiments pinpointed 12 genes that were significantly and consistently upregulated in pleomorphic adenomas and in PLAG1-expressing cells, identifying them as putative PLAG1 targets in these tumors.

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Section: Discussionmentioning

confidence: 99%

Microarray screening for target genes of the proto-oncogene PLAG1

et al. 2004

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“…Cytokines requiring a short coreceptor ␣ chain (IL-6, IL-11, IL-12, IL-23, IL-27, CNTF, and CLC) bind first to this subunit through a site I located in the CBD portion of the receptor (17,19,(55)(56)(57)(58)(59)(60). 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).…”

Section: Discussionmentioning

confidence: 99%

“…All share the common gp130 signaling receptor in their multimeric receptors (11). Depending on the identity of the activating ligand, gp130 can either homodimerize in the presence of IL-6 or IL-11 (12,13) or associate with a related type I cytokine receptor, LIF receptor (LIFR) (14), when recruited by LIF, OSM, CNTF, cardiotrophin-1, or cardiotrophin-like cytokine (15)(16)(17)(18)(19). OSM can also activate a specific receptor implicating OSM receptor (OSMR) (20).…”

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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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104

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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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“…Several residues showed significant chemical shift perturbations (Ͼ0.04 ppm for CNTFR BC and Ͼ0.023 ppm for gp130 BC) of their NMR signals after binding. DISCUSSION CNTF and its specific receptor, CNTFR, are increasing in importance due to the recent findings that CNTF may have a significant role in the treatment of obesity and diabetes (6), demyelinating central nervous system disease (7), and the identification of cardiotrophin-like cytokine/cytokine-like factor-1 as the long hypothesized second ligand for CNTFR (42). Unlike IL-6 and IL-11, CNTF has an asymmetric signaling complex, involving gp130 and LIFR, and so must contain some receptor-receptor interactions different from those seen in the IL-6 complex (14,21).…”

Section: Figmentioning

confidence: 99%

Solution Structure of the C-terminal Domain of the Ciliary Neurotrophic Factor (CNTF) Receptor and Ligand Free Associations among Components of the CNTF Receptor Complex

Man

Sze

et al. 2003

Journal of Biological Chemistry

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The functional receptor complex of ciliary neurotrophic factor (CNTF), a member of the gp130 family of cytokines, is composed of CNTF, the CNTF receptor ␣ (CNTFR), gp130, and the leukemia inhibitory factor receptor (LIFR). However, the nature of the receptor-mediated interactions in this complex has not yet been resolved. To address this issue we have determined the solution structure of the C-terminal or BC domain of CNTFR and studied the interactions of CNTFR with LIFR and gp130. We reported previously that the membrane distal cytokine-binding domain (CBD1) of LIFR could interact in vitro with soluble CNTFR (sCNTFR) in the absence of CNTF. Here we show that the CBD of human gp130 can also bind in vitro to sCNTFR in the absence of CNTF. In addition, the gp130 CBD could compete with the LIFR CBD1 for the binding of sCNTFR. Substitution of residues in the gp130 CBD, the LIFR CBD1, and the CNTFR BC domain that are expected to be involved in receptor-receptor interactions significantly reduced their interactions. An NMR chemical shift perturbation study of the interaction between the BC domains of CNTFR and gp130 further mapped the interaction surface. These data suggest that both the gp130 CBD and the LIFR CBD1 interact with CNTFR in a similar way and provide insights into the nature of the CNTF receptor complex.

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CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex

Cited by 230 publications

References 32 publications

Microarray screening for target genes of the proto-oncogene PLAG1

Microarray screening for target genes of the proto-oncogene PLAG1

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

Solution Structure of the C-terminal Domain of the Ciliary Neurotrophic Factor (CNTF) Receptor and Ligand Free Associations among Components of the CNTF Receptor Complex

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