Elson, G.C. et al. CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat. Neurosci. 3, 867-872

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


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.
    Full-text · Article · Jul 2015 · Cytokine & growth factor reviews
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    • "Interleukin (IL)-11 is a member of the IL-6 family of cytokines that comprises nine secreted soluble ligands; IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin-M (OSM), ciliaryneurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), interleukin-27 (IL-27) and interleukin-31 (IL-31) [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]. "
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    ABSTRACT: Interleukin (IL)-11 is a member of the IL-6 family of cytokines that is defined by the shared use of the GP130 signal transducing receptor subunit. In addition of its long recognized activities as a hemopoietic growth factor, IL-11 has an emerging role in epithelial cancer biology. Through the activation of the GP130-Janus kinase signaling cascade and associated transcription factor STAT3, IL-11 can confer many of the tumor intrinsic 'hallmark' capabilities to neoplastic cells, if they express the ligand-specific IL-11Rα receptor subunit. Accordingly, IL-11 signaling has recently been identified as a rate-limiting step for the growth tumors arising from the mucosa of the gastrointestinal tract. However, there is less appreciation for a potential role of IL-11 to support breast cancer progression, apart from its well documented capacity to facilitate bone metastasis. Here we review evidence that IL-11 expression in breast cancer correlates with poor disease outcome and discuss some of the molecular mechanisms that are likely to underpin these observations. These include the capacity of IL-11 to stimulate survival and proliferation of cancer cells alongside angiogenesis of the primary tumor and of metastatic progenies at distant organs. We review current strategies to interfere with IL-11 signaling and advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jul 2015 · Cytokine & growth factor reviews
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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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    ABSTRACT: Unlike mammals, zebrafish can regenerate a damaged retina. This remarkable regenerative response is mediated by Müller glia (MG) that undergo a reprogramming event that drives their proliferation and the generation of multipotent progenitors for retinal repair. The mechanisms that drive MG reprogramming are poorly understood. Here, we report that Leptin and Gp130-coupled receptors, acting via a Jak/Stat signaling pathway, stimulate MG reprogramming and progenitor formation in the injured retina. Importantly, we find that ascl1a gene expression, which drives MG reprogramming in fish and mammals, is regulated in a Jak/Stat-dependent manner and requires consensus Stat-binding sites for injury-dependent activation. Finally, we identify cytokines that are induced by retinal injury and exhibit a remarkable synergy in their ability to activate Jak/Stat signaling and MG reprogramming in the uninjured retina. Our study not only furthers our understanding of retina regeneration in zebrafish but also suggests new strategies for awakening retina regeneration in mammals.
    Full-text · Article · Sep 2014 · Cell Reports
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