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

Centre d'Immunologie Pierre Fabre, 5 Avenue Napoleon III, 74164 St. Julien-en-Genevois, France.
Nature Neuroscience (Impact Factor: 16.1). 10/2000; 3(9):867-72. DOI: 10.1038/78765
Source: PubMed

ABSTRACT Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, CNTFR, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (CLC) and the soluble receptor cytokine-like factor-1 (CLF). CLF expression was required for CLC secretion, and the complex acted only on cells expressing functional CNTF receptors. The CLF/CLC complex activated gp130, LIFR and signal transducer and activator of transcription 3 (STAT3) and supported motor neuron survival. Our results indicate that the CLF/CLC complex is a second ligand for CNTFR with potentially important implications in nervous system development.

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    • "Although CLCF1 contains a signal sequence [2], its secretion is inefficient unless co-expressed with its chaperone CRLF1, a protein that contains no transmembrane or cytoplasmic domain [1] [7] [9]. Alternatively, sCNTFR may act as a chaperone, in the same manner as CRLF1 [6] (Fig. 1). "
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    ABSTRACT: Mutations in cardiotrophin-like cytokine factor (CLCF1) and the related cytokine to which it binds, cytokine receptor-like factor 1 (CRLF1), are associated with Crisponi/cold induced sweating syndromes, and lead to early neonatal death in mice due to a suckling defect. These cytokines are members of the IL-6 superfamily, and form a range of composite cytokines that signal through gp130 bound either to the ciliary neurotrophic factor receptor (CNTFR) or a complex that involves the IL-27 p28 subunit. This review describes current knowledge of the signalling complexes formed by these cytokines, and explores their described and suggested roles in the neural, haematopoietic, skeletal, renal, immune and respiratory systems during development and adulthood, and in degenerative diseases and cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine & growth factor reviews 07/2015; DOI:10.1016/j.cytogfr.2015.07.014 · 5.36 Impact Factor
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    • "However, MG and MG-derived progenitors do express RNAs encoding receptors for these IL-6 family cytokines (Figures 4B, S5A, and S5B). Furthermore, genes encoding the alternative Cntf receptor ligand, Clcf1/Crlf1a (Elson et al., 2000), are highly induced in the injured retina (Figures 4A, 4B, and S5A). Therefore , Clcf1/Crlf1a may be responsible for Cntf receptor activation in the injured retina. "
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    Cell Reports 09/2014; 9(1). DOI:10.1016/j.celrep.2014.08.047 · 8.36 Impact Factor
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    • "Crisponi syndrome is now considered to be the same disorder as cold-induced sweating syndrome [103], and cold-induced sweating syndrome is caused by mutations in the CLCF-1 or CRLF-1 genes [9]. CLCF-1 binds with either CRLF-1 (cytokine receptor-like factor-1) or sCNTFR (soluble ciliary neurotrophic factor receptor) and then competes with CNTF (ciliary neurotrophic factor) for the receptor complex composed of CNTFR, LIFR and gp130 (Figure 3; [51,104,105]). Therefore, it seems that the dysautomonic symptoms seen in STWS are caused by a lack of CLCF-1/CRLF-1 signaling due to a mutated LIFR gene [13,21]. "
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    ABSTRACT: Stuve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.
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