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Gene Review

CLCF1  -  cardiotrophin-like cytokine factor 1

Homo sapiens

Synonyms: B-cell-stimulating factor 3, BSF-3, BSF3, CISS2, CLC, ...
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Disease relevance of CLCF1


High impact information on CLCF1

  • These phenotypes firmly established the roles CLC channels play in stabilizing the plasma membrane voltage in muscle and possibly in neurons, in the transport of salt and fluid across epithelia, in the acidification of endosomes and synaptic vesicles, and in the degradation of bone by osteoclasts [5].
  • The opening and closing of the vertebrate CLC channels are also known to couple to the permeant ions via their binding sites in the ion-permeation pathway [4].
  • Mouse models revealed blindness and infertility as further consequences of CLC gene disruptions [5].
  • A synthetic peptide (NR6) based on the phosphorylation site sequence was phosphorylated readily by NR kinase (NRk) in vitro [6].
  • CLC chloride channels: correlating structure with function [7].

Chemical compound and disease context of CLCF1


Biological context of CLCF1


Anatomical context of CLCF1

  • So far, the known functions of NNT-1/BSF-3 encompass neurotrophic and B cell stimulatory effects, as well as neuroimmunoendocrine modulation of corticotroph function [11].
  • NNT-1/BSF-3 mRNA is found mainly in lymph nodes and spleen [1].
  • The purpose of this study was to evaluate the biological effects and signalling pathways that are induced by BSF-3 in malignant plasma cells [3].
  • The CLC family comprises a group of integral membrane proteins whose major action is to translocate chloride (Cl-) ions across the cell membranes [4].
  • Neither pulmonary nor cutaneous mast cells stained for CLC protein or MBP [9].

Associations of CLCF1 with chemical compounds

  • In the present study, we demonstrate that a fusion protein comprising CLC covalently coupled through a glycine/serine linker to sCNTFR (CC-FP) is efficiently secreted from transfected mammalian cells [13].
  • Previous experimental natural abundance deuterium (NAD) NMR results have shown an odd/even-related alternation in the ((2)H/(1)H) ratio of the methylene groups of fatty acids (ChemBioChem 2001, 2, 425) and, by NAD NMR in CLC, a marked difference between enantiotopic deuterons for each methylenic site (Anal. Chem. 2004, 76, 2827) [14].
  • A CLC-type chloride channel gene is required for laccase activity and virulence in Cryptococcus neoformans [15].
  • Synergism Between Halide Binding and Proton Transport in a CLC-type Exchanger [16].
  • Taken together, these data suggested that the NO resistance in HL-NR6 cells is associated with the increased Cu,Zn-SOD/catalase and that NO-mediated apoptosis in HL-60 cells is correlated with the generation of ROS and derived molecules like peroxynitrite [17].

Physical interactions of CLCF1

  • Importantly, we found that CLC interacts with the soluble forms of CNTFRalpha and CLF via sites 1 and 3, respectively [18].

Regulatory relationships of CLCF1

  • Incubation of AtT-20 cells with 10 ng/ml recombinant human NNT-1/BSF-3 rapidly induced tyrosine-phosphorylation of signal transducer and activator of transcription (STAT)3 and STAT1 at 5 and 10 min [19].
  • In comparison with untreated control, NNT-1/BSF-3 significantly stimulated ACTH secretion at 24 and 48 h 1.7 +/- 0.2-fold and 1.5 +/- 0.1-fold above baseline [19].
  • BSF-3 stimulated cell growth could not be inhibited by neutralizing anti-IL-6 or anti-IL-6 receptor antibodies, but was abrogated by anti-gp130 antibodies [3].

Other interactions of CLCF1

  • Our data indicate that the activation of the Jak-STAT cascade is essential for corticotroph NNT-1/BSF-3 signaling [19].
  • In summary, we have shown that NNT-1/BSF-3 is a modulator of corticotroph cell function, which is negatively regulated by SOCS-3 [19].
  • Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3 [19].
  • Functionally active fusion protein of the novel composite cytokine CLC/soluble CNTF receptor [13].
  • Surprisingly, the residues that are important for the interaction of CLC with CLF are part of the conserved FXXK motif of site 3 known to be the interaction site of LIFRbeta [18].

Analytical, diagnostic and therapeutic context of CLCF1

  • The recent crystallization of bacterial CLC proteins gave surprising insights into CLC Cl(-)-channel permeation and gating and provides an excellent basis for structure-function studies [20].
  • Whereas mAb 806 displayed antitumor activity against NR6 xenografts, mAb 528 therapy was ineffective, suggesting that mAb 528 mediates its antitumor activity by disrupting interactions between the de2-7 and wild-type EGFR [21].
  • Western blot analysis verified the expression of CLC channels, as well as KCNK5 [22].
  • Murine motor neuron-like (NSC-34) cell cultures expressed full-length and truncated p75(NTR), tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog-2 (NHR2) but were TrkA deficient [23].
  • BACKGROUND: Recently, techniques using fine-caliber instruments (2 or 3 mm in diameter) for laparoscopic cholecystectomy, called minilaparoscopic cholecystectomy (MLC), were reported to be superior to conventional LC (CLC, using 5 mm instruments) in postoperative course and cosmetic outcome [24].


  1. Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Senaldi, G., Varnum, B.C., Sarmiento, U., Starnes, C., Lile, J., Scully, S., Guo, J., Elliott, G., McNinch, J., Shaklee, C.L., Freeman, D., Manu, F., Simonet, W.S., Boone, T., Chang, M.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component. Lelièvre, E., Plun-Favreau, H., Chevalier, S., Froger, J., Guillet, C., Elson, G.C., Gauchat, J.F., Gascan, H. J. Biol. Chem. (2001) [Pubmed]
  3. Functional significance of novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) for human myeloma cell growth and survival. Burger, R., Bakker, F., Guenther, A., Baum, W., Schmidt-Arras, D., Hideshima, T., Tai, Y.T., Shringarpure, R., Catley, L., Senaldi, G., Gramatzki, M., Anderson, K.C. Br. J. Haematol. (2003) [Pubmed]
  4. Structure and function of clc channels. Chen, T.Y. Annu. Rev. Physiol. (2005) [Pubmed]
  5. Physiological functions of CLC Cl- channels gleaned from human genetic disease and mouse models. Jentsch, T.J., Poët, M., Fuhrmann, J.C., Zdebik, A.A. Annu. Rev. Physiol. (2005) [Pubmed]
  6. Identification of Ser-543 as the major regulatory phosphorylation site in spinach leaf nitrate reductase. Bachmann, M., Shiraishi, N., Campbell, W.H., Yoo, B.C., Harmon, A.C., Huber, S.C. Plant Cell (1996) [Pubmed]
  7. CLC chloride channels: correlating structure with function. Estévez, R., Jentsch, T.J. Curr. Opin. Struct. Biol. (2002) [Pubmed]
  8. Computational EST database analysis identifies a novel member of the neuropoietic cytokine family. Shi, Y., Wang, W., Yourey, P.A., Gohari, S., Zukauskas, D., Zhang, J., Ruben, S., Alderson, R.F. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  9. Differences between basophils and mast cells: failure to detect Charcot-Leyden crystal protein (lysophospholipase) and eosinophil granule major basic protein in human mast cells. Leiferman, K.M., Gleich, G.J., Kephart, G.M., Haugen, H.S., Hisamatsu, K., Proud, D., Lichtenstein, L.M., Ackerman, S.J. J. Immunol. (1986) [Pubmed]
  10. Human CLC-KB gene promoter drives the EGFP expression in the specific distal nephron segments and inner ear. Kobayashi, K., Uchida, S., Okamura, H.O., Marumo, F., Sasaki, S. J. Am. Soc. Nephrol. (2002) [Pubmed]
  11. Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)--a novel gp130 cytokine with pleiotropic functions. Vlotides, G., Zitzmann, K., Stalla, G.K., Auernhammer, C.J. Cytokine Growth Factor Rev. (2004) [Pubmed]
  12. Inactivation of cardiotrophin-like cytokine, a second ligand for ciliary neurotrophic factor receptor, leads to cold-induced sweating syndrome in a patient. Rousseau, F., Gauchat, J.F., McLeod, J.G., Chevalier, S., Guillet, C., Guilhot, F., Cognet, I., Froger, J., Hahn, A.F., Knappskog, P.M., Gascan, H., Boman, H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Functionally active fusion protein of the novel composite cytokine CLC/soluble CNTF receptor. Guillet, C., Lelièvre, E., Plun-Favreau, H., Froger, J., Chabbert, M., Hermann, J., Benoit de Coignac, A., Bonnefoy, J.Y., Gascan, H., Gauchat, J.F., Elson, G. Eur. J. Biochem. (2002) [Pubmed]
  14. Assignment of absolute configuration of natural abundance deuterium signals associated with (R)- and (S)-enantioisotopomers in a fatty acid aligned in a chiral liquid crystal: enantioselective synthesis and NMR analysis. Baillif, V., Robins, R.J., Billault, I., Lesot, P. J. Am. Chem. Soc. (2006) [Pubmed]
  15. A CLC-type chloride channel gene is required for laccase activity and virulence in Cryptococcus neoformans. Zhu, X., Williamson, P.R. Mol. Microbiol. (2003) [Pubmed]
  16. Synergism Between Halide Binding and Proton Transport in a CLC-type Exchanger. Accardi, A., Lobet, S., Williams, C., Miller, C., Dutzler, R. J. Mol. Biol. (2006) [Pubmed]
  17. Resistance to nitric oxide-mediated apoptosis in HL-60 variant cells is associated with increased activities of Cu,Zn-superoxide dismutase and catalase. Yabuki, M., Kariya, S., Ishisaka, R., Yasuda, T., Yoshioka, T., Horton, A.A., Utsumi, K. Free Radic. Biol. Med. (1999) [Pubmed]
  18. Two different contact sites are recruited by cardiotrophin-like cytokine (CLC) to generate the CLC/CLF and CLC/sCNTFRalpha composite cytokines. Perret, D., Guillet, C., Elson, G., Froger, J., Plun-Favreau, H., Rousseau, F., Chabbert, M., Gauchat, J.F., Gascan, H. J. Biol. Chem. (2004) [Pubmed]
  19. Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3. Auernhammer, C.J., Isele, N.B., Kopp, F.B., Spoettl, G., Cengic, N., Weber, M.M., Senaldi, G., Engelhardt, D. Endocrinology (2003) [Pubmed]
  20. CLC chloride channels and transporters. Jentsch, T.J., Neagoe, I., Scheel, O. Curr. Opin. Neurobiol. (2005) [Pubmed]
  21. The efficacy of epidermal growth factor receptor-specific antibodies against glioma xenografts is influenced by receptor levels, activation status, and heterodimerization. Johns, T.G., Perera, R.M., Vernes, S.C., Vitali, A.A., Cao, D.X., Cavenee, W.K., Scott, A.M., Furnari, F.B. Clin. Cancer Res. (2007) [Pubmed]
  22. Characterization of vectorial chloride transport pathways in the human pancreatic duct adenocarcinoma cell line HPAF. Fong, P., Argent, B.E., Guggino, W.B., Gray, M.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  23. Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. Turner, B.J., Murray, S.S., Piccenna, L.G., Lopes, E.C., Kilpatrick, T.J., Cheema, S.S. J. Neurosci. Res. (2004) [Pubmed]
  24. Early minilaparoscopic cholecystectomy in patients with acute cholecystitis. Hsieh, C.H. Am. J. Surg. (2003) [Pubmed]
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