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Gene Review

CNTF  -  ciliary neurotrophic factor

Homo sapiens

Synonyms: Ciliary neurotrophic factor, HCNTF
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Disease relevance of CNTF


Psychiatry related information on CNTF


High impact information on CNTF


Chemical compound and disease context of CNTF


Biological context of CNTF

  • Unlike other cytokine receptors studied to date, the receptors for the CNTF cytokine family utilize all known members of the Jak-Tyk family, but induce distinct patterns of Jak-Tyk phosphorylation in different cell lines [19].
  • Thus, we have identified a protein complex binding to a novel DNA sequence that is necessary for full CNTF induction of VIP gene transcription [20].
  • Mutations in an 8-bp sequence (TTACTGGA) eliminated binding of this protein complex and markedly reduced transcriptional activation of the CyRE by CNTF [20].
  • Similarly, we also characterized two additional antibodies B-P8 and B-P4, which inhibited the TF1 cell proliferation observed in the presence of CNTF and IL-11, respectively [21].
  • Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology [22].

Anatomical context of CNTF

  • The physiological and pathophysiological functions of neurotrophins and CNTF are discussed in the context of their potential use for the treatment of traumatic and degenerative diseases of the peripheral and central nervous systems [23].
  • Such dimers are likely to be relevant to the storage of CNTF in the peripheral nerve given the high concentrations present in this tissue [24].
  • Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity [25].
  • Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve [26].
  • GPAR alpha mRNA expression is largely restricted to the nervous system and was detected in all neurons that have been shown to respond to GPA or CNTF by increased survival or differentiation, i.e. ciliary, sympathetic, sensory dorsal root, motoneurons, retinal ganglion cells and amacrine cells [27].

Associations of CNTF with chemical compounds


Physical interactions of CNTF


Enzymatic interactions of CNTF

  • A STAT3 peptide was efficiently phosphorylated on Ser727 in a CNTF-dependent manner by mTOR, but not by a kinase-inactive mTOR mutant or by p70 S6 kinase [29].

Regulatory relationships of CNTF


Other interactions of CNTF

  • However, it is unlikely that they play a role in engaging the three distinct receptor subunits that comprise the CNTF receptor, given the low concentration of extracellular CNTF and its high potency [24].
  • The D1 structural motif, located at the beginning of the D-helix of human CNTF, contains two amino acid residues, F152 and K155, which are conserved among all cytokines that signal through LIFR [36].
  • CDF/LIF is a polyfunctional cytokine that shares a remarkable overlap with ciliary neurotrophic factor in its actions on neurons, and with interleukin-6 in its actions on other tissues [37].
  • Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) [26].
  • However, IL-6 and CNTF do not exhibit this cross-talk ability [38].

Analytical, diagnostic and therapeutic context of CNTF


  1. The ciliary neurotrophic factor receptor alpha component induces the secretion of and is required for functional responses to cardiotrophin-like cytokine. Plun-Favreau, H., Elson, G., Chabbert, M., Froger, J., deLapeyrière, O., Lelièvre, E., Guillet, C., Hermann, J., Gauchat, J.F., Gascan, H., Chevalier, S. EMBO J. (2001) [Pubmed]
  2. Integration of Jak-Stat and AP-1 signaling pathways at the vasoactive intestinal peptide cytokine response element regulates ciliary neurotrophic factor-dependent transcription. Symes, A., Gearan, T., Eby, J., Fink, J.S. J. Biol. Chem. (1997) [Pubmed]
  3. Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling. Ziotopoulou, M., Erani, D.M., Hileman, S.M., Bjørbaek, C., Mantzoros, C.S. Diabetes (2000) [Pubmed]
  4. Localization of the gene for the ciliary neurotrophic factor receptor (CNTFR) to human chromosome 9. Donaldson, D.H., Britt, D.E., Jones, C., Jackson, C.L., Patterson, D. Genomics (1993) [Pubmed]
  5. Neurotrophins and their receptors in nerve injury and repair. Ebadi, M., Bashir, R.M., Heidrick, M.L., Hamada, F.M., Refaey, H.E., Hamed, A., Helal, G., Baxi, M.D., Cerutis, D.R., Lassi, N.K. Neurochem. Int. (1997) [Pubmed]
  6. 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, D., He, W., Sze, K.H., Gong, K., Smith, D.K., Zhu, G., Ip, N.Y. J. Biol. Chem. (2003) [Pubmed]
  7. Long-term lentiviral-mediated expression of ciliary neurotrophic factor in the striatum of Huntington's disease transgenic mice. Zala, D., Bensadoun, J.C., Pereira de Almeida, L., Leavitt, B.R., Gutekunst, C.A., Aebischer, P., Hayden, M.R., Déglon, N. Exp. Neurol. (2004) [Pubmed]
  8. Neurotrophins and ciliary neurotrophic factor: their biology and pathology. Sariola, H., Sainio, K., Arumäe, U., Saarma, M. Ann. Med. (1994) [Pubmed]
  9. Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease. Mittoux, V., Joseph, J.M., Conde, F., Palfi, S., Dautry, C., Poyot, T., Bloch, J., Deglon, N., Ouary, S., Nimchinsky, E.A., Brouillet, E., Hof, P.R., Peschanski, M., Aebischer, P., Hantraye, P. Hum. Gene Ther. (2000) [Pubmed]
  10. Relation of weight maintenance and dietary restraint to peroxisome proliferator-activated receptor gamma2, glucocorticoid receptor, and ciliary neurotrophic factor polymorphisms. Vogels, N., Mariman, E.C., Bouwman, F.G., Kester, A.D., Diepvens, K., Westerterp-Plantenga, M.S. Am. J. Clin. Nutr. (2005) [Pubmed]
  11. Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. DeChiara, T.M., Vejsada, R., Poueymirou, W.T., Acheson, A., Suri, C., Conover, J.C., Friedman, B., McClain, J., Pan, L., Stahl, N., Ip, N.Y., Yancopoulos, G.D. Cell (1995) [Pubmed]
  12. A null mutation in the human CNTF gene is not causally related to neurological diseases. Takahashi, R., Yokoji, H., Misawa, H., Hayashi, M., Hu, J., Deguchi, T. Nat. Genet. (1994) [Pubmed]
  13. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Allsopp, T.E., Wyatt, S., Paterson, H.F., Davies, A.M. Cell (1993) [Pubmed]
  14. Opposing regulation of ciliary neurotrophic factor receptors on neuroblastoma cells by distinct differentiating agents. Malek, R.L., Halvorsen, S.W. J. Neurobiol. (1997) [Pubmed]
  15. Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons. Kaur, N., Lu, B., Monroe, R.K., Ward, S.M., Halvorsen, S.W. J. Neurochem. (2005) [Pubmed]
  16. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Kokoeva, M.V., Yin, H., Flier, J.S. Science (2005) [Pubmed]
  17. Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress. Monroe, R.K., Halvorsen, S.W. Free Radic. Biol. Med. (2006) [Pubmed]
  18. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Watt, M.J., Dzamko, N., Thomas, W.G., Rose-John, S., Ernst, M., Carling, D., Kemp, B.E., Febbraio, M.A., Steinberg, G.R. Nat. Med. (2006) [Pubmed]
  19. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Stahl, N., Boulton, T.G., Farruggella, T., Ip, N.Y., Davis, S., Witthuhn, B.A., Quelle, F.W., Silvennoinen, O., Barbieri, G., Pellegrini, S. Science (1994) [Pubmed]
  20. Identification of a novel gp130-responsive site in the vasoactive intestinal peptide cytokine response element. Jones, E.A., Conover, J., Symes, A.J. J. Biol. Chem. (2000) [Pubmed]
  21. Interleukin-6 family of cytokines induced activation of different functional sites expressed by gp130 transducing protein. Chevalier, S., Fourcin, M., Robledo, O., Wijdenes, J., Pouplard-Barthelaix, A., Gascan, H. J. Biol. Chem. (1996) [Pubmed]
  22. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. Kallen, K.J., Grötzinger, J., Lelièvre, E., Vollmer, P., Aasland, D., Renné, C., Müllberg, J., Myer zum Büschenfelde, K.H., Gascan, H., Rose-John, S. J. Biol. Chem. (1999) [Pubmed]
  23. The changing scene of neurotrophic factors. Thoenen, H. Trends Neurosci. (1991) [Pubmed]
  24. Crystal structure of dimeric human ciliary neurotrophic factor determined by MAD phasing. McDonald, N.Q., Panayotatos, N., Hendrickson, W.A. EMBO J. (1995) [Pubmed]
  25. Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity. Raju, S.V., Zheng, M., Schuleri, K.H., Phan, A.C., Bedja, D., Saraiva, R.M., Yiginer, O., Vandegaer, K., Gabrielson, K.L., O'donnell, C.P., Berkowitz, D.E., Barouch, L.A., Hare, J.M. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  26. Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Mufson, E.J., Kroin, J.S., Sendera, T.J., Sobreviela, T. Prog. Neurobiol. (1999) [Pubmed]
  27. Analysis of function and expression of the chick GPA receptor (GPAR alpha) suggests multiple roles in neuronal development. Heller, S., Finn, T.P., Huber, J., Nishi, R., Geissen, M., Püschel, A.W., Rohrer, H. Development (1995) [Pubmed]
  28. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Davis, S., Aldrich, T.H., Stahl, N., Pan, L., Taga, T., Kishimoto, T., Ip, N.Y., Yancopoulos, G.D. Science (1993) [Pubmed]
  29. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Yokogami, K., Wakisaka, S., Avruch, J., Reeves, S.A. Curr. Biol. (2000) [Pubmed]
  30. Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor. Gutman, C.R., Strittmatter, W.J., Weisgraber, K.H., Matthew, W.D. J. Neurosci. (1997) [Pubmed]
  31. The tails of two proteins: the scrapie prion protein and the ciliary neurotrophic factor receptor. Stahl, N., Boulton, T.G., Ip, N., Davis, S., Yancopoulos, G.D. Braz. J. Med. Biol. Res. (1994) [Pubmed]
  32. Neurotrophic factors and their receptors. Ip, N.Y., Yancopoulos, G.D. Ann. Neurol. (1994) [Pubmed]
  33. Ciliary neurotrophic factor and phorbol ester each decrease selected STAT3 pools in neuroblastoma cells by proteasome-dependent mechanisms. Malek, R.L., Halvorsen, S.W. Cytokine (1999) [Pubmed]
  34. Ciliary neurotrophic factor combined with soluble receptor inhibits synthesis of proinflammatory cytokines and prostaglandin-E2 in vitro. Shapiro, L., Panayotatos, N., Meydani, S.N., Wu, D., Dinarello, C.A. Exp. Cell Res. (1994) [Pubmed]
  35. Regulation of tyrosine hydroxylase gene expression in IMR-32 neuroblastoma cells by basic fibroblast growth factor and ciliary neurotrophic factor. Rabinovsky, E.D., Ramchatesingh, J., McManaman, J.L. J. Neurochem. (1995) [Pubmed]
  36. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists. Di Marco, A., Gloaguen, I., Graziani, R., Paonessa, G., Saggio, I., Hudson, K.R., Laufer, R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  37. The emerging neuropoietic cytokine family: first CDF/LIF, CNTF and IL-6; next ONC, MGF, GCSF? Patterson, P.H. Curr. Opin. Neurobiol. (1992) [Pubmed]
  38. Cross-talk among gp130 cytokines in adipocytes. Zvonic, S., Baugh, J.E., Arbour-Reily, P., Mynatt, R.L., Stephens, J.M. J. Biol. Chem. (2005) [Pubmed]
  39. Reciprocal regulation of ciliary neurotrophic factor receptors and acetylcholine receptors during synaptogenesis in embryonic chick atria. Wang, X., Halvorsen, S.W. J. Neurosci. (1998) [Pubmed]
  40. A ciliary neurotrophic factor-sensitive human myeloma cell line. Gu, Z.J., Zhang, X.G., Hallet, M.M., Lu, Z.Y., Wijdenes, J., Rossi, J.F., Klein, B. Exp. Hematol. (1996) [Pubmed]
  41. Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma. Wierzbowska, A., Urbańska-Ryś, H., Robak, T. Br. J. Haematol. (1999) [Pubmed]
  42. Enhanced neurotrophin synthesis and molecular differentiation in non-transformed human retinal progenitor cells cultured in a rotating bioreactor. Kumar, R., Dutt, K. Tissue engineering. (2006) [Pubmed]
  43. Signaling pathway of ciliary neurotrophic factor in neuroblastoma cell lines. Kuroda, H., Sugimoto, T., Horii, Y., Sawada, T. Med. Pediatr. Oncol. (2001) [Pubmed]
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