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

Nature Neuroscience volume 3, pages 867–872 (2000)Cite this article

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 α chain, CNTFR, and two signaling β 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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Figure 1: CLF and CLC form a stable secreted complex.
Figure 2: CLF/CLC uses the functional CNTF receptor.
Figure 3: Physical interaction between CLF/CLC and CNTFR.
Figure 4: CLF/CLC and CNTF compete for the CNTFR.
Figure 5: Tyrosine phosphorylation of gp130, LIFR and STAT 3 in SK-N-GP and HepG2 cells.
Figure 6: CLF/CLC supports the survival of rat embryonic motor neurons in vitro.

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Acknowledgements

E.L. is supported by an Association Française contre les Myopathies (AFM) grant. The authors thank K.J. Kallen at the University of Mainz, Germany for providing transfected Ba/F3 cell lines, V. Steimle at the Max-Planck Institute for Immunobiology, Freiburg, Germany for providing the pEBS-PL expression vector and C. Lacheny and F. Derouet for preparation of the anti-c-myc antibody.

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  1. Greg C. A. Elson, Eric Lelièvre and Catherine Guillet: The first three authors contributed equally to this work

Authors and Affiliations

  1. Centre d'Immunologie Pierre Fabre, 5 Avenue Napoleon III, 74164 St, Julien-en-Genevois, France

    Greg C. A. Elson, Amélie Benoit de Coignac, Yves Delneste, Jean-Yves Bonnefoy & Jean-François Gauchat

  2. INSERM E 9928, CHU Angers, Batiment Monteclair, 4 Rue Larrey, Angers, 49033, France

    Eric Lelièvre, Catherine Guillet, Sylvie Chevalier, Hélène Plun-Favreau, Josy Froger, Isabelle Suard & Hugues Gascan

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Correspondence to Jean-François Gauchat.

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Elson, G., Lelièvre, E., Guillet, C. et al. CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat Neurosci 3, 867–872 (2000). https://doi.org/10.1038/78765

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